APOE-ε4 Genotype and Western Diet Synergistically Aggravate Synaptic Dysfunction in Alzheimer’s Disease via D-serine Disruption

doi:10.21203/rs.3.rs-7320776/v1

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Research Article

APOE-ε4 Genotype and Western Diet Synergistically Aggravate Synaptic Dysfunction in Alzheimer’s Disease via D-serine Disruption

https://doi.org/10.21203/rs.3.rs-7320776/v1

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Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder thought to result from complex interactions between genetic and environmental risk factors. The APOE-ε4 allele is the strongest genetic contributor to late-onset AD, while a Western diet - high in saturated fats and refined sugars - is a major lifestyle-related risk factor associated with AD progression. However, how these two factors interact at an early stage of the disease remains unclear. In this study, we examined their combined impact on hippocampal synaptic transmission and plasticity in an AD mouse model and evaluated whether supplementation with d-serine, the key NMDAR co-agonist, could reverse the resulting deficits.

Methods

To assess the combined effects of genetic and dietary risk factors on synaptic function, we crossed APP/PS1 mice with APOE-ε4 KI mice andgenerated four mouse lines: wild-type, APP/PS1, APOE-ε4, and APP/PS1/APOE-ε4. Hippocampal synaptic transmission and plasticity, NMDAR function and d- and l-serine levels were evaluated using a combination of electrophysiological recordings, pharmacological interventions and capillary electrophoresis in brain slices, under either control or Western diet conditions.

Results

A significant impairment of both basal excitatory synaptic transmission and long-term potentiation (LTP) was detected in APP/PS1 mice by 9 months of age. These deficits were significantly more pronounced in APP/PS1/APOE-ε4 mice. Notably, Western diet accelerated these impairments, with significant deficits already present at 7 months in both APOE-ε4 and APP/PS1/APOE-ε4 mice. Mechanistically, these impairments were associated with reduced d-serine availability and NMDAR hypofunction at CA3-CA1 synapses.

Conclusions

This study provides the first direct evidence of a specific and synergistic interaction between the APOE-ε4 genotype and Western diet in advancing and exacerbating hippocampal synaptic dysfunction in an AD mouse model. These findings highlight d-serine/NMDAR signaling as a key mechanistic pathway through which genetic and environmental risk factors converge in early AD, and underscore the potential of targeting astrocytic d-serine biosynthetic pathways as a promising therapeutic strategy for APOE-ε4 carriers at risk for late-onset AD.

Trial registration

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Alzheimer’s disease

APOE-ε4

Western diet

NMDAR

d-serine

hippocampus

synaptic plasticity

APP/PS1 mice

gene-environment interaction.

Alzheimer’s disease (AD) is the most common chronic neurodegenerative disorder, clinically characterized by a progressive decline of cognitive functions such as learning and memory, ultimately leading to severe dementia and functional decline. It is estimated that over 50 million people worldwide are affected by AD, with projections suggesting this number will double by 2040 (source: www.alz.co.uk). Although the exact etiology remains debated, hallmark pathological features include impaired glucose metabolism, followed by accumulation of extracellular amyloid-beta (Aβ) plaques, intracellular neurofibrillary tangles, and inflammation - ultimately culminating in neuronal impairment and death (1, 2). Synaptic dysfunction, particularly in the limbic cortex, is believed to play a central role in disease progression. Memory impairments in AD are closely associated with reduced synaptic density and efficacy, especially in the hippocampus, where glutamatergic synapses are highly vulnerable (3–5).

Several studies have reported early synaptic deficits in AD, notably at hippocampal glutamatergic synapses, including reduced dendritic spine density and impaired long-term potentiation (LTP), a key form of synaptic plasticity critical for learning and memory and among the earliest functions disrupted in AD (6, 7). LTP at CA3-CA1 synapses is primarily mediated by postsynaptic NMDA receptor activation, which initiates intracellular signaling cascades that enhance synaptic strength and connectivity (8, 9). Its early disruption in AD underscores the vulnerability of these synapses and highlights LTP impairment as a key pathological hallmark. We have previously shown that deficits in synaptic plasticity and memory in the triple-transgenic mouse model (3xTg-AD) are linked to reduced astrocytic glycolysis and therefore reduced biosynthesis of l-serine and d-serine (10, 11). As an essential co-agonist of synaptic NMDA receptors (NMDARs) at hippocampal CA3-CA1 synapses (12–14), d-serine plays a key role in NMDAR-dependent synaptic plasticity. Accordingly, reduced d-serine availability has been consistently associated with impaired NMDAR function and cognitive decline in both AD models (15, 16) and during normal aging (17).

While most transgenic models of AD reflect familial (early-onset) forms, which account for only 5–10% of cases (18), the majority of AD cases are sporadic and late-onset. The strongest genetic risk factor for late-onset AD is the presence of the apolipoprotein E ɛ4 allele (APOE-ɛ4) (19, 20), which increases the risk of AD by 3- to 15-fold (21–23). Though the exact mechanisms by which APOE-ɛ4 promotes AD are still under investigation, evidence suggests it contributes to increased Aβ deposition, cerebrovascular dysfunction, and altered cerebral metabolism (24, 25). In APOE-ε4 knock-in mice, impairments in synaptic plasticity, reductions in dendritic spine density, and increased neuronal hyperexcitability have been observed, further implicating APOE-ε4 in AD-related synaptic vulnerability (26–28).

Beyond genetic predisposition, environmental factors such as diet significantly influence late-onset AD risk. Both clinical and preclinical evidence strongly associate Western dietary patterns - characterized by high levels of saturated fats, refined sugars, and low nutrient content - with cognitive decline and increased AD susceptibility (reviewed in (29, 30). Notably, Western diet-induced pathologies such as neuroinflammation, glial activation, and Aβ accumulation overlap mechanistically with those linked to APOE-ɛ4 (31, 32). However, the specific interactions between APOE-ɛ4 and Western diet in modulating synaptic transmission and plasticity in AD remain poorly understood.

We hypothesized that the combination of genetic risk (APOE-ɛ4, APP, PS1) and acquired risk (Western diet, aging) factors would exacerbate synaptic pathology in an AD mouse model. To test this, we investigated hippocampal synaptic transmission and plasticity in APP/PS1 mice, with and without the APOE-ɛ4 allele, under control diet or Western diet conditions. Our findings demonstrate for the first time that the APOE-ɛ4 genotype amplifies, and a Western diet intake accelerates, hippocampal synaptic deficits in APP/PS1 mice through a synergistic interaction. Remarkably, these impairments were rescued by exogenous d-serine supplementation, implicating disrupted d-serine biosynthesis and impaired NMDAR-dependent plasticity as key mechanisms underlying this gene-environment interaction.

Animals

APPswe/PS1dE9 (APP/PS1) mice, a widely used model of Alzheimer’s disease (AD) (25), were obtained from The Jackson Laboratory (strain number 034832-JAX). APOE-ε4 KI, a mouse line pertinent to AD and atherosclerosis, with human APOE-ε4 sequences replacing those on the mouse APOE gene (24), was also obtained from The Jackson Laboratory (strain number 027894-JAX). These two lines were crossed to generate four genotypes: wild-type (wt), APP/PS1, APOE-ε4, and APP/PS1/APOE-ε4. Mice of either sex were used in all experiments. All procedures were conducted in strict accordance with the European Union directive 2010/63/EU for animal care and use, and were approved by the French Ministry of Agriculture and Fisheries and the local ethical committee. Every effort was made to minimize animal suffering. Animal care was overseen by veterinarians and trained technicians specialized in rodent husbandry. Animals were housed under standard environmental conditions (12-h light-dark cycle, temperature: 22 ± 1°C and humidity: 50%) with ad libitum access to food and water. Ex vivo electrophysiological experiments were conducted at a fixed period during the light phase in a genotype experimenter-blind approach.

Diet

Wild-type (wt), APP/PS1, APOE-ε4, and APP/PS1/APOE-ε4 mice were housed in genotype-specific cages and provided ad libitum access to either a control diet or a Western diet. The control standard diet (A03, Safe, Augy, France) contained: 21% protein, 5% vegetable fat, 4% sucrose, and provided 3.4 kcal/g. The Western diet (TD.88137, Envigo Teklad, UK) was formulated to mimic human dietary patterns associated with metabolic dysfunction. It contained: 17% protein, 21% animal fat, 34% sucrose, 0.2% cholesterol, and provided 4.5 kcal/g. The diet was enriched in high-fructose corn syrup, saturated fats, and low fiber, with reduced micronutrient density and elevated milk protein. Dietary protocols were as follows: Mice in the control diet group received the standard diet continuously from birth until experimental evaluation. Mice in the Western diet group were maintained on the control diet until 5 months of age, after which the Western diet was introduced:

For animals evaluated at 7 months, the Western diet was administered for 2 months (from 5 to 7 months of age), based on prior evidence that short-term Western diet exposure increases oxidative stress and alters metabolic markers in APP/PS1 models (33).
For animals evaluated at 11 months, the Western diet was administered for 6 months (from 5 to 11 months of age), following studies showing that longer-term Western diet impairs cognition and promotes Aβ-related pathology in AD rodent models (34).

Body weight was routinely monitored throughout the dietary intervention period to assess metabolic impact and ensure animal well-being.

Slice preparation

Brain hippocampal slices were obtained from 5, 7, 9 and 11 month-old wt, APP/PS1, APOE-ε4 and APP/PS1/APOE-ε4 mice, as described previously (10, 14, 35). Animals were anesthetized with isoflurane and the brain rapidly removed and placed in ice-cold oxygenated artificial cerebrospinal fluid (aCSF) solution continuously gassed with carbogen (95% O₂ and 5% CO₂) containing the following (in mM): 125 NaCl, 2.5 KCl, 1.25 NaH2PO4, 26 NaHCO₃, 10 glucose, 1.3 MgCl₂, 2 CaCl₂, (pH = 7.3–7.4; 305–310 mOsmol/kg). A block of tissue containing the hippocampus was extracted and sliced with a VT1200S vibratome (Leica VT1200S, Leica Biosystems, Nussloch, Germany). Acute transverse slices (350 µm thick) of the dorsal hippocampus were obtained by sectioning the brain at ~ 45° from the coronal plane. The slices were transferred to a submersion recovery chamber with oxygenated aCSF at 33°C for 30 min and afterwards allowed to cool to room temperature and rest for 60 min minimum before experimentation. Following recovery period, hippocampal slices were transferred to a recording chamber installed on a BX50 fluorescence microscope (Olympus, Tokio, Japan), and held in place by a nylon mesh completely submerged and continuously perfused with gassed aCSF solution at a constant flow (3 mL/min) and temperature (32–33°C).

Electrophysiology

Borosilicate glass (GC150F-7.5, Harvard Apparatus, Holliston, MA) capillaries, enclosing the recording microelectrodes, were pulled on a PP-83 vertical puller (Narishige, Tokyo, Japan) and the resulting pipettes filled with aCSF (series resistance 3–5 MΩ). The CA3-CA1 hippocampal areas were identified with differential interference contrast light microscopy with a 4x Plan Achromat objective (Olympus).

Field-excitatory postsynaptic potentials (fEPSPs) were evoked by orthodromic stimulation (100 ms duration) of afferent CA3 Schaffer collaterals using a concentric bipolar tungsten electrode (CBARC75, FHC, Bowdoin, USA) placed in the proximal CA1 region, > 200 µm away from the extracellular recording electrodes, located in the stratum radiatum of the distal CA1 area, close to the subiculum. To assess basal synaptic transmission efficiency, an input/output protocol was used where synaptic fEPSPs were evoked at a constant rate of 0.03 Hz stimulation of Schaffer collaterals (1 stimuli at 30 s intervals) using incremental 1V stimulation intensities (0-10V) and the resulting fEPSPs slope measured as a function of stimulus intensity. The fEPSPs slope was calculated as a linear fit of the rising phase, between time points set in the baseline period and corresponding to 20% and 60% of the peak amplitude. Data from three consecutive fEPSPs were collected for each stimulation intensity. To analyze pre-synaptic activity, we performed a paired-pulse protocol consisting in two consecutive stimuli separated by 50 ms, delivered every 30 s. The paired-pulse ratio (PPR) between the slopes of the two consecutive fEPSPs (fEPSP2/fEPSP1) was quantified.

LTP experiments were done as previously (10, 11, 14). Briefly, fEPSPs were evoked at a constant rate of 0.03 Hz with the stimulus intensity set at 30–40% of the maximum amplitude without triggering population spikes. After obtaining a stable baseline for at least 20 min (< 10% change), LTP was induced by applying a high frequency stimulation (HFS) protocol (100 Hz for 1 s, repeated three times at 20 s intervals). After LTP induction, fEPSPs were recorded for > 60 min. The change in the slope of the fEPSP was evaluated 50–60 min post-HFS and normalized to the slope measured during the 10 min immediately before HFS. Post-tetanic potentiation (PTP) was assessed as the average fEPSPs slope obtained in the first 3 min after LTP induction.

Electrophysiological recordings of the NMDAR-component of fEPSPs (NMDAR-fEPSPs) were done as previously (10, 14, 36). Briefly, the NMDAR contribution was extracted from global fEPSPs using picrotoxin (100 µM), NBQX (10 µM) and low external Mg²⁺ concentration (0.2 mM) in the perfused aCSF, to block GABA receptors, AMPA/kainate receptors and remove the NMDAR Mg²⁺ channel block, respectively. In some experiments, d-serine (50 µM) was directly applied in the perfused aCSF, immediately after the baseline period for NMDAR-fEPSPs and 20 min before recording input/output and LTP experiments, and then continuously present thorough the experiment.

Data were acquired using a Multiclamp 700A amplifier (Molecular Devices, Sunnyvale, CA) controlled with pCLAMP 10 software (Molecular Devices) on current-clamp mode. Recordings were filtered at 2 kHz and digitized at 10 kHz using a Digidata 1322A digitizer interface (Axon Instruments, Inc.) and continuously stored on a personal computer. Data were collected and analyzed online and offline, respectively, using Clampfit from pCLAMP 10 software.

Measurement of Amino Acids in Hippocampal Extracellular medium

For the simultaneous measurement of d-serine, l-serine and glycine, a laser-induced fluorescence capillary electrophoresis detection method was employed as previously (14, 36, 37). Briefly, brain hippocampal transverse 350 µm slices obtained from 7-month-old wt, APP/PS1, APOE-ε4 and APP/PS1/APOE-ε4 mice were transferred to a submersion recovery chamber with oxygenated aCSF at 33°C for 45 min. Extracellular medium was quickly removed, frozen using liquid nitrogen and stored at -80°C.

Extracellular levels of d-serine, l-serine and glycine were then determined. Briefly, pooled slices were deproteinized by addition of cold trichloroacetic acid (TCA) to a 4% final concentration. The suspension was centrifuged at 16,800 g for 10 min to pellet the protein content used for protein quantification. TCA was then removed from the supernatant with water-saturated diethyl ether and stored at -80°C. Samples were analyzed with a commercial laser-induced fluorescence capillary electrophoresis (CE-LIF) (CE: Beckman Coulter (Brea, California, US), P/ACE MDQ; LIF: Picometrics (Labège, France)), LIF-UV-02, 410 nm 20 mW) as follows: samples were processed for micellar CE-LIF and were fluorescently derivatized at RT for 60 min with napthalene-2,3-dicarboxaldehyde (NDA) before being analyzed by CE using a hydroxypropyl-b-cyclodextrin (HP-b-CD) based chiral separation buffer. All electropherograms data were collected and analyzed using Karat 32 software v8.0 (Beckman Coulter, France). The amounts of d-serine, l-serine and glycine were normalized to the protein content determined from pooled hippocampal slices by the Lowry method using the BCA protein Pierce assay (ThermoScientific, CA, USA) assay with bovine serum albumin (BSA) as a standard. The quantity of d-serine, l-serine and glycine in the samples was determined from a standardized curve while peak identification was made according the retention time of reference standards and by spiking the fraction with the amino acid.

Drugs and chemicals

Stock solutions were made and diluted with appropriate solvent before bath application. Drugs used were d-serine, l-serine, glycine (50 µM, Sigma-Aldrich, Merck, Germany), NMDA-R antagonist APV/AP-5 (10 µM, Tocris Bioscience, UK), AMPA and kainate receptors antagonist NBQX (10 µM, Tocris Bioscience), GABA_AR selective antagonist picrotoxin (100 µM, Tocris Bioscience). Unless stated otherwise all remaining saline medium components and reagents were purchased from Sigma-Aldrich.

Data collection and statistical analyses

No statistical method was used to predetermine sample size. Sample size was chosen based on prior experience for each experiment, to yield adequate power to detect specific effects. To avoid possible bias, data collection and analysis was performed blind.

Data are expressed as mean ± SEM of the n number of independent experimental units (with N number of animals and n number of slices). All data were analyzed using GraphPad Prism software (Versions 5.0 and 8.0, GraphPad, USA). Data were first screened for a Gaussian distribution with Kolmogorov-Smirnov test: normal distributed data with one independent variable (e.g. genotype) was analyzed using one-way ANOVA followed by Dunnett’s or Tukey’s parametric post hoc tests for multiple-comparisons or two-tailed t-test for dual-comparisons; normal distributed data with two or more independent variables (e.g. genotype, voltage) was analyzed using two-way ANOVA followed by Bonferroni’s multiple-comparison parametric post hoc test; non-normal distributed data was analyzed by Dunn’s multiple-comparison non-parametric post hoc test. The significance level was set at a 95% confidence level with *p < 0.05.

Hippocampal Basal Synaptic Transmission Is Impaired in APP/PS1/APOE-ɛ4 Mice

The cortico-hippocampal circuitry, particularly the glutamatergic synapses between CA3 and CA1 regions, plays a central role in hippocampal-dependent memory processing (38). Disruption or loss of these synapses contributes to explicit memory impairments, a hallmark early cognitive deficit in AD (3, 4). To investigate whether basal synaptic transmission is influenced by the APOE-ɛ4 genotype in the context of AD, we crossed APPswe/PS1dE9 mice - a widely used model of familial (early-onset) AD (25), with APOE-ɛ4 knock-in (APOE-ɛ4-ki) mice, which carry the most significant genetic risk factor for sporadic (late-onset) AD (24).

We generated four mouse lines: wt, APP/PS1, APOE-ɛ4, and APP/PS1/APOE-ɛ4, and evaluated hippocampal basal synaptic transmission at 5, 7, 9, and 11 months (Fig. 1a-d). Synaptic transmission at CA3-CA1 synapses was assessed using an input/output (I/O) protocol, measuring the slope of the field excitatory postsynaptic potentials (fEPSPs), which reflects excitatory transmission primarily mediated by AMPA and kainate receptors.

In wt mice, input/output (I/O) relationships remained stable across ages, at 5 (Fig. 1a), 7 (Fig. 1b), 9 (Fig. 1c), and 11 months (Fig. 1d) - with the complete data summarized in Fig. 1f. Across the evaluation period, APOE-ε4 mice exhibited mild but non-significant reductions in synaptic transmission, while APP/PS1 mice showed transient significant deficits at 7 months (Fig. 1c and 1f, 0.48 ± 0.04 vs wt 0.66 ± 0.07 mV/ms at 10 V stimulation, n = 17, p < 0.05) that were not sustained at 9 or 11 months - findings consistent with previous reports on both APPswe/PS1dE9 and APOE-ɛ4-ki mice (7, 39, 40).

In contrast, APP/PS1/APOE-ɛ4 mice exhibited significant deficits in basal synaptic transmission beginning at 7 months (Fig. 1c and 1f, 0.46 ± 0.04 vs wt 0.66 ± 0.07 mV/ms at 10 V stimulation, n = 17, p < 0.05), which became more pronounced at 9 months (Fig. 1d and Fig. 1f, 0.43 ± 0.05 vs wt 0.74 ± 0.07 mV/ms at 10 V stimulation, n = 15, p < 0.01) and 11 months (Fig. 1e and 1f, 0.34 ± 0.05 vs wt 0.63 ± 0.10 mV/ms at 10 V stimulation, n = 9, p < 0.01). These synaptic impairments were unlikely to be caused by changes in presynaptic release probability, as the paired-pulse ratio remained stable across genotypes and ages, with values consistently above 1.5, indicating intact presynaptic function and a low basal release probability typical of CA3-CA1 synapses (Fig. 1g). Together, these results suggest that the synergistic interaction between the APP/PS1 and APOE-ɛ4 genotypes, but not either genotype alone, drives progressive basal synaptic transmission dysfunction from 7 months onward.

APOE-ɛ4 Genotype Exacerbates Hippocampal Synaptic Plasticity Deficits in APP/PS1 Mice

Early synaptic plasticity dysfunction is a hallmark of AD, with deficits in CA3-CA1 activity dependent long-term potentiation (LTP) observed in various AD models, including APP/PS1 mice (39, 41). Although APOE-ɛ4 has also been linked with synaptic dysfunction (26–28), its specific impact on LTP deficits in AD models remains incompletely characterized.

To address this, we recorded LTP in acute hippocampal slices from wild-type (wt), APP/PS1, APOE-ɛ4 knock-in, and APP/PS1/APOE-ɛ4 mice at 5, 7, 9, and 11 months of age. LTP was induced at CA3-CA1 synapses using a 100 Hz high-frequency stimulation (HFS) protocol applied three times to the Schaffer collaterals, and synaptic potentiation was considered when the fEPSPs slopes measured in between 50 to 60 minutes were increased (Fig. 2a).

Our data indicate that both wt and APOE-ɛ4 mice exhibited stable LTP across all time points, in contrast to earlier studies reporting LTP deficits in APOE-ɛ4 knock-in models (26, 40, 42). In APP/PS1 mice, however, significant LTP deficits emerged at 9 months (Fig. 2c and 2f, 140.58 ± 4.00% vs wt 155.54 ± 2.33%, n = 9, p < 0.05), and became more pronounced at 11 months (Fig. 2d and 2f, 133.02 ± 1.72% vs wt 152.97 ± 2.36%, n = 10, p < 0.01), consistent with previous reports in the APPswe/PS1dE9 AD model (43–47). Importantly, APP/PS1/APOE-ɛ4 mice exhibited a significantly greater reduction in LTP compared to APP/PS1 alone, as reflected by a marked reduction at 9 months (Fig. 2c and 2f, 128.39 ± 2.00% vs wt 155.54 ± 2.33%, n = 18, p < 0.001), which declined even further at 11 months (Fig. 2d and 2f, 120.41 ± 4.30% vs wt 155.54 ± 2.33%, n = 8, p < 0.0001).

These findings demonstrate that the APOE-ɛ4 genotype significantly exacerbates synaptic plasticity deficits in APP/PS1 mice, supporting a synergistic interaction between familial (APP/PS1) and sporadic (APOE-ɛ4) genetic risk factors in the progression of hippocampal synaptic dysfunction in late-onset AD.

D-Serine Rescues Impaired NMDAR-Mediated Synaptic Plasticity in APP/PS1/APOE-ɛ4 Mice

LTP depends on the activation of synaptic NMDA receptors (NMDARs), and disruptions in NMDAR function are thought to contribute to early synaptic deficits in AD. Previous studies have shown that Aβ and its derivatives directly reduce synaptic NMDAR activity, a phenomenon also observed in AD patients and animal models (48–51). Additionally, APOE-ɛ4 has been implicated in altered regulation of synaptic NMDAR regulation in AD (26, 52).

To investigate NMDAR dysfunction in our model, we recorded the NMDAR component of field excitatory postsynaptic potentials (NMDAR-fEPSPs) at CA3-CA1 synapses in 9-month-old mice, the time point when LTP deficits were first observed (see Fig. 2d and f).

Wild-type (wt) and APOE-ɛ4 mice showed comparable NMDAR-fEPSP I/O curves (Fig. 3b). APP/PS1 mice exhibited a modest but non-significant reduction, whereas APP/PS1/APOE-ɛ4 mice displayed a significant decrease in NMDAR-fEPSP slopes (Fig. 3b, 0.037 ± 0.004 vs wt 0.080 ± 0.015 mV/ms at 20 V stimulation, n = 9, p < 0.05;), indicating greater NMDAR dysfunction due to the APOE-ɛ4 genotype.

Because d-serine - the endogenous co-agonist of synaptic NMDARs - is essential for NMDAR-dependent LTP and memory, and is known to be reduced in 3xTg-AD mice (10), we next evaluated the co-agonist binding site occupancy of synaptic NMDARs. Following 30 minutes of baseline NMDAR-fEPSP recordings, bath application of d-serine (50 µM) induced moderate and comparable increases in NMDAR-fEPSPs in both wt (Fig. 3c, 137.85 ± 12.86% of baseline, n = 8) and APOE-ɛ4 mice (Fig. 3c, 135.12 ± 14.71% of baseline, n = 8). These results are consistent with previous findings suggesting that NMDAR co-agonist sites at CA3-CA1 synapses are not fully saturated under basal conditions, particularly in AD models (10, 13). In APP/PS1 mice, d-serine application resulted in a more pronounced increase in NMDAR-fEPSPs (Fig. 3c, 163.83 ± 11.78% of baseline, n = 9), and this effect was significantly greater in APP/PS1/APOE-ɛ4 mice (Fig. 3c, 179.23 ± 9.90%, n = 10, p < 0.05 vs wt), indicating a lower baseline occupancy of NMDAR co-agonist sites. These findings are consistent with the reduced NMDAR activity observed in APP/PS1/APOE-ɛ4 mice (Fig. 3b) and suggest a deficiency in synaptic d-serine availability.

We hypothesized that such d-serine deficits contribute to the LTP impairments seen in 9-month-old APP/PS1 and APP/PS1/APOE-ɛ4 mice (Fig. 2d). In support of this, LTP impairments in APP/PS1 and APP/PS1/APOE-ɛ4 mice were significantly rescued when exogenous d-serine (50 µM) was applied in the perfused aCSF (Fig. 3d, e). d-serine enhanced LTP across all genotypes but had a particularly strong recovery effect in APP/PS1 mice (control: 140.58 ± 4.00% vs d-serine: 161.34 ± 8.87%, n = 9, p < 0.05) and even more so in APP/PS1/APOE-ɛ4 mice (control: 128.39 ± 2.00% vs d-serine: 158.93 ± 5.94%, n = 9, p < 0.01) (Fig. 3e). These results point to reduced d-serine availability as a key mechanism underlying NMDAR hypofunction and impaired synaptic plasticity in APP/PS1/APOE-ɛ4 mice.

Western diet Accelerates Synaptic Plasticity Deficits in APOE-ɛ4-carrier Mice

In addition to the well-established genetic risk conferred by the APOE-ɛ4 allele, lifestyle factors-particularly dietary habits-can significantly exacerbate susceptibility to late-onset AD (53). While high-fat diets have previously been associated with hippocampal synaptic plasticity impairments (54, 55), the impact of the more complex Western diet - characterized by high levels of saturated fats, refined sugars, synthetic additives, and reduced protein content - on hippocampal synaptic function, especially in the presence of the APOE-ɛ4 genotype, remains poorly understood.

To investigate this interaction, we exposed wt, APP/PS1, APOE-ɛ4, and APP/PS1/APOE-ɛ4 mice to either a standard control diet or a custom-formulated Western diet. We then assessed basal synaptic transmission and LTP in hippocampal slices (Fig. 4a). The Western diet was introduced at 5 months of age and maintained for 2 months, a time window previously shown to induce neuropathological alterations in AD mouse models (33, 56). The 7-month time point was selected as it precedes the typical onset of synaptic plasticity deficits in this model (Fig. 2c, d) (34).

Interestingly, basal synaptic transmission was elevated across all genotypes on Western diet exposure compared to their respective control-diet counterparts (Fig. 4b, c). At 7 months of age, significant increases in basal transmission were observed in wt (p < 0.05), APP/PS1 (p < 0.01), APOE-ɛ4 (p < 0.05), and APP/PS1/APOE-ɛ4 (p < 0.05) mice on the Western diet. Despite this general enhancement, APP/PS1/APOE-ɛ4 mice still displayed impaired basal synaptic transmission relative to wt mice on the same diet (0.75 ± 0.06 vs. 1.05 ± 0.09 mV/ms, n = 11, p < 0.05; Fig. 4b, c). Moreover, APOE-ɛ4 mice fed a Western diet also exhibited synaptic deficits compared to wt mice on the same diet (0.75 ± 0.07 vs. 1.05 ± 0.09 mV/ms, n = 9, p < 0.05), a phenotype not observed under control diet conditions. These findings suggest that while Western diet intake broadly increases basal synaptic activity across genotypes, it does not normalize or reverse synaptic vulnerability in APOE-ɛ4 genotype carriers.

Interestingly, the Western diet induced synaptic plasticity deficits at an earlier time point. At 7 months of age, while LTP remained intact under control diet conditions (Fig. 2c, Fig. 4e), significant impairments were observed in APOE-ɛ4 (131.83 ± 7.13% vs. wt 158.42 ± 4.31%, n = 9, p < 0.05) and APP/PS1/APOE-ɛ4 mice (128.70 ± 5.00% vs. wt 158.42 ± 4.31%, n = 16, p < 0.05) following Western diet intake (Fig. 4d, e). Similar deficits were also observed at 11 months of age (data not shown), suggesting that these impairments persist beyond the early onset phase. Thus, just two months of Western diet exposure were sufficient to advance the onset of LTP deficits in APP/PS1/APOE-ɛ4 mice from 9 months (Fig. 2d, f) to 7 months (Fig. 4d, e), and to unmask previously absent impairments in APOE-ɛ4 mice. Notably, LTP in wt and APP/PS1 mice remained unaffected by the Western diet. These findings suggest that the Western diet selectively interacts with the APOE-ɛ4 genotype to advance and precipitate hippocampal synaptic plasticity deficits.

d-Serine Restores NMDAR-Dependent Synaptic Plasticity From Deficits Present in APOE-ɛ4-carrier Mice on a Western Diet

Given that d-serine effectively rescued NMDAR-dependent synaptic plasticity deficits in 9-month-old APP/PS1 and APP/PS1/APOE-ɛ4 mice under control diet conditions (Fig. 3), we next investigated whether a similar d-serine deficiency was involved in the LTP impairments observed at 7 months in mice fed a Western diet (Fig. 4). To this end, we assessed synaptic NMDAR activity by recording the NMDAR component of field EPSPs (NMDAR-fEPSPs) using an I/O protocol in hippocampal slices from 7-month-old mice maintained on either control or Western diet (Fig. 5b, c).

Under control diet conditions, all genotypes exhibited comparable NMDAR-fEPSP I/O curves (Fig. 5b). In contrast, Western diet (Fig. 5a-c) led to a significant reduction in NMDAR-mediated synaptic responses in APP/PS1 (0.006 ± 0.01 mV/ms, n = 10, p < 0.05), APOE-ɛ4 (0.055 ± 0.004 mV/ms, n = 14, p < 0.01), and APP/PS1/APOE-ɛ4 mice (0.047 ± 0.004 mV/ms, n = 11, p < 0.001), relative to wt mice on the same diet (0.077 ± 0.01 mV/ms, n = 10). This contrasts with the increased basal synaptic transmission observed under Western diet in Fig. 4b, suggesting that the previous general fEPSP enhancement is not mediated by NMDARs, but likely reflects increased AMPAR or kainate-driven excitability. These findings suggest that APOE-ɛ4 genotype carriers are particularly vulnerable to NMDAR hypofunction under Western diet conditions.

To assess whether reduced d-serine availability contributes to the observed NMDAR hypofunction, we evaluated co-agonist site occupancy at synaptic NMDARs by applying exogenous d-serine (50 µM) to hippocampal slices from 7-month-old mice under either control or Western diet conditions (Fig. 5d, e). Under control diet conditions, all genotypes responded similarly to d-serine application after 30 min, indicating comparable baseline co-agonist site occupancy. However, under Western diet exposure, d-serine elicited significantly greater increases in NMDAR-fEPSPs in APOE-ɛ4 (173.0 ± 8.0%, n = 13, p < 0.05) and APP/PS1/APOE-ɛ4 mice (182.0 ± 9.0%, n = 10, p < 0.001) relative to wt controls (143.0 ± 4.0%, n = 15). These findings suggest that Western diet reduces endogenous d-serine availability in APOE-ɛ4 carriers, thereby limiting NMDAR activation and contributing to synaptic dysfunction.

To confirm whether reduced NMDAR function was associated with altered co-agonist availability, we quantified extracellular levels of d-serine, l-serine (its biosynthetic precursor), and glycine from hippocampal slice perfusates using capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) (Fig. 6a). This method enables precise, simultaneous quantification of amino acids in small volume samples, providing insights into receptor ligand dynamics (36, 57, 58). Under control diet conditions, extracellular concentrations of d-serine, l-serine, and glycine did not differ significantly across genotypes, indicating preserved amino acid homeostasis in the hippocampus (Fig. 6b, d, f). In contrast, Western diet exposure led to a marked reduction in d-serine and l-serine extracellular levels specifically in APP/PS1/APOE-ɛ4 mice, while glycine remained unaffected. d-serine levels in these mice dropped significantly compared to their control diet counterparts (0.057 ± 0.003 nmol/mg vs. 0.076 ± 0.005 nmol/mg, p < 0.05; Fig. 6c), as did levels of its biosynthetic precursor l-serine (1.602 ± 0.086 nmol/mg vs. 2.140 ± 0.167 nmol/mg, p < 0.05; Fig. 6e). In contrast, glycine concentrations remained stable across all genotypes and dietary conditions (Fig. 6g), suggesting that the observed NMDAR co-agonist deficiency is specific to the d-serine pathway. These results further support that Western diet selectively impairs d-serine metabolism in APP/PS1/APOE-ɛ4 mice, contributing to reduced NMDAR activation and synaptic dysfunction.

Given the observed reductions in d-serine levels and d-serine-dependent NMDAR activity, we next tested whether exogenous d-serine (Fig. 7) could restore the impaired synaptic function observed in 7-month-old APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice fed with a Western diet (Fig. 4). Interestingly, d-serine application (50 µM) effectively rescued LTP impairments in both APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice fed a Western diet (Fig. 7b). In APOE-ɛ4 mice, LTP was significantly improved following d-serine treatment (Fig. 7c, Western diet: 131.83 ± 7.13% vs. Western diet + d-serine: 160.46 ± 6.30%, n = 9, p < 0.05;), and a similar rescue was observed in APP/PS1/APOE-ɛ4 mice (Fig. 7c, Western diet: 128.70 ± 5.00% vs. Western diet + d-serine: 155.91 ± 4.08%, n = 10, p < 0.05).

Our results show that exogenous d-serine not only rescued LTP deficits in 9-month-old APP/PS1 and APP/PS1/APOE-ɛ4 mice under control diet conditions (Fig. 3), but also mitigated the synaptic plasticity impairments induced by Western diet in 7-month-old APOE-ɛ4 and APP/PS1/APOE-ɛ4 mice (Fig. 7). These effects support a role for reduced d-serine availability in the synaptic deficits observed across genotypes and diet conditions, particularly in the presence of APOE-ɛ4 and Western diet.

Synaptic dysfunction is recognized as a central and early feature of AD, often preceding overt amyloid plaque deposition, tau pathology, or neuronal loss (59–61). Reductions in hippocampal synaptic density, alterations in dendritic spine morphology, and impairments in synaptic plasticity, particularly long-term potentiation (LTP), are tightly linked to cognitive decline (5, 6, 41, 62). Although transgenic mouse models have provided invaluable insights into these processes, they fall short of recapitulating the complexity of sporadic, late-onset AD, which accounts for more than 95% of AD cases (41). Notably, few models integrate both genetic and modifiable lifestyle risk factors - such as the APOE-ε4 allele and Western dietary patterns - that better reflect real-world vulnerability. To address this, we combined APOE-ε4 expression and Western diet exposure in APP/PS1 mice, providing a model that may more closely reflect the pathophysiological conditions underlying early synaptic dysfunction.

Although APOE-ε4 is the strongest genetic risk factor for late-onset AD, its effects on synaptic function remain incompletely understood (19, 20). APOE-ε4 knock-in mice show increased Aβ burden, impaired amyloidal clearance, and heightened neuroinflammation (63–65). Even without amyloid pathology, APOE-ε4 mice exhibit early, sex-dependent cognitive and behavioral changes (52, 66–68), accompanied by reduced synaptic markers and spine density (69–71). However, studies of synaptic physiology in APOE-ε4 models have been inconsistent, with some reporting impaired synaptic transmission (72, 73) and LTP (26, 40, 42), while others found no deficits or even enhancements (74–76), possibly reflecting different experimental conditions, mice strains or age. In our study, APOE-ε4 mice under control diet showed no synaptic impairment, consistent with previous reports (74–76). However, the combination of APOE-ε4 and APP/PS1 mutations led to progressive deficits in synaptic transmission and LTP, with impairments in synaptic transmission emerging at 7 months and LTP deficits appearing by 9 months under control diet conditions, suggesting that APOE-ε4 aggravates synaptic vulnerability in the context of amyloid pathology (Figs. 1 and 2). These findings highlight a synergistic interaction between APOE-ε4 and amyloidogenic pathology in the early synaptic pathogenesis of AD. Our data further reveal that the impaired synaptic plasticity observed in APP/PS1/APOE-ɛ4 mice is strongly associated with NMDAR hypofunction, likely derived from reduced availability of d-serine, the essential co-agonist at synaptic NMDARs (Fig. 3). These findings align with our previous work showing that d-serine supplementation restores LTP and memory in 3xTg-AD mice (10), and supports synaptic NMDAR function in other AD models (15, 16). Notably, exogenous d-serine rescued both NMDAR-mediated responses and LTP deficits in APP/PS1 and APP/PS1/APOE-ɛ4 mice, underscoring the therapeutic potential of targeting d-serine signaling in early AD-related synaptic pathology.

While high-fat diets have been shown to disrupt synaptic plasticity and cognitive performance (54, 55, 77), far less is known about the effects of a full Western diet, which more closely mimics modern dietary patterns and real-world risk by combining high levels of saturated fat, refined sugars, synthetic additives, and reduced protein. Epidemiological studies have increasingly linked Western diet consumption to an elevated risk of AD (29, 30, 78). While its long-term metabolic consequences - such as obesity, insulin resistance, and cardiovascular disease - are well documented (29, 30, 78), the specific mechanisms through which Western diet impacts brain function, particularly in the early stages of AD and in interaction with the APOE-ε4 genotype, remain poorly defined. In the brain, Western diet has been associated with increased Aβ accumulation, glial activation, blood-brain barrier dysfunction and neuroinflammation (31, 32). However, its direct influence on synaptic physiology, especially under APOE-ε4-related vulnerability, is still largely unexplored.

We found that just two months of Western diet intake is sufficient to precipitate significant hippocampal synaptic plasticity deficits in APOE-ε4 and APP/PS1/APOE-ε4 mice - deficits not observed under control diet conditions at this age (Fig. 4). This early onset of LTP impairment, alongside the induction of synaptic deficits in APOE-ε4 carriers, supports a synergistic interaction between diet and genotype, as previously suggested (78). Importantly, this occurred without affecting LTP in WT or APP/PS1 mice, highlighting a selective vulnerability of APOE-ε4 carriers.

In regards to basal synaptic transmission, Western diet increased fEPSPs across all genotypes; however, APOE-ε4 carriers continued to show weaker transmission compared to wt and APP/PS1 mice (Fig. 4), indicating that Western diet does not normalize intrinsic genotype-dependent basal transmission vulnerability. While high-fat diets have been linked to hippocampal baseline neurotransmission impairments (79, 80), Western diet intake, consistent with our findings, has conversely been associated with increased basal neuronal excitability in various brain regions (81, 82). This supports a complex, multifaceted impact of Western diet on hippocampal function - particularly in APOE-ɛ4 carriers - distinct from the effects observed with more simplified high-fat diets. Notably, despite the general enhancement in fEPSPs slopes, NMDAR-mediated responses were significantly reduced in APOE-ε4, APP/PS1, and APP/PS1/APOE-ε4 mice (Fig. 5), suggesting that the increased basal synaptic transmission under Western diet is likely driven by AMPAR or kainate-driven excitability, not NMDARs. This selective NMDAR hypofunction, particularly in APOE-ε4 carriers, may underlie the failure to sustain synaptic plasticity. To our knowledge, this is the first evidence that Western diet alone is sufficient to induce synaptic plasticity dysfunction in APOE-ε4 carriers, where such deficits were absent under control diet conditions, and advances their onset in APP/PS1/APOE-ε4 mice.

Our data further reveal that the synaptic vulnerability observed in APOE-ε4 carriers under Western diet conditions is tightly linked to reduced availability of d-serine (15, 16). While synaptic NMDAR responses remained intact under control diet across all genotypes, Western diet exposure significantly reduced NMDAR-mediated transmission in APOE-ε4 and APP/PS1/APOE-ε4 mice (Fig. 5), supporting the view that these genotypes are especially susceptible to diet-induced glutamatergic disruption (83–85). Importantly, this NMDAR hypofunction was associated with a greater potentiation of NMDAR-fEPSPs following exogenous d-serine application, suggesting a deficit in endogenous co-agonist availability. Supporting this, CE-LIF biochemical analysis confirmed significantly reduced extracellular d-serine and its biosynthetic precursor l-serine in the hippocampus of Western diet-fed APP/PS1/APOE-ε4 mice, while glycine levels remained unchanged (Fig. 6).

While d-serine has been consistently shown to support cognitive function in aging-related decline (86–88), its role in AD remains more controversial. Across various AD models and patient cohorts, some studies have reported reduced d-serine levels and beneficial effects following supplementation (10, 15, 16, 89–92). In contrast, others have found elevated d-serine levels linked to excitotoxicity and disease progression (93–97), while a few report no significant changes at all (98, 99). These discrepancies likely reflect differences in AD mouse models, their underlying glycolytic and metabolic states, or the disease stage in patient samples. In general, d-serine appears beneficial in prodromal and early-phase AD - approximately 4–8 months in APP/PS1 mice - but may exert deleterious effects in intermediate and late disease stages (86–88, 100, 101). Here, we showed that _D-serine supplementation fully rescued LTP deficits at 7 months in both APOE-ε4 and APP/PS1/APOE-ε4 mice (Fig. 7), and also restored function in older animals (9–11 months) under control diet (Fig. 3). This suggests that in the APP/PS1/APOE4 model, NMDAR hypofunction persists beyond early stages, potentially extending the therapeutic window for l-serine or d-serine intervention. These results align with our previous findings that both l- and d-serine levels are reduced in AD patients and in 6–7-month-old 3xTg-AD mice, and that l- and d-serine supplementation can restore synaptic plasticity and memory function in the 3xTg-AD model (10). This reduction in d-serine was linked to altered astrocytic glycolytic flux and disruption of l-serine biosynthesis, observed in both human and animal models (10, 101, 102).

d- and l-serine reductions observed in APP/PS1/APOE-ε4 mice likely reflect a shift in astrocytic metabolism toward aerobic glycolysis, a pattern independently induced by both APOE-ε4 expression and Western diet (103, 104). Notably, rodents exposed to high-fat and Western diets (104–108), as well as APOE4-expressing astrocytes (84, 104, 109–111), exhibit similarly reprogrammed metabolic profiles - marked by decreased oxidative metabolism and reduced biosynthetic capacity - suggesting a shared vulnerability that may converge on serine metabolism. These combined stressors likely divert glycolytic flux away from the phosphorylated pathway of l-serine synthesis (102, 104), thereby diminishing NMDAR co-agonist availability and compromising astrocyte-neuron metabolic coupling (10, 112, 113).

Interestingly, while d-serine has therapeutic potential, its clinical use is limited by nephrotoxicity concerns, particularly in rodents (114). l-serine, by contrast, shares neuroprotective effects in AD and aging - supporting protein homeostasis, anti-inflammatory responses, and synaptic resilience - with a more favorable safety profile (10, 89, 115). Thus, targeting astrocytic l-serine biosynthesis may offer a safer route for therapeutic intervention in APOE-ε4 carriers.

Together, these results highlight the convergence of genetic (APOE-ε4) and environmental (Western diet) risk factors on d-serine/NMDAR signaling as a key mechanistic pathway in early synaptic dysfunction in AD, and a potential target for therapeutic strategies.

Our study provides new mechanistic insight into how the APOE-ε4 genotype and Western diet synergistically aggravate and accelerate hippocampal synaptic dysfunction through disruption of d-serine/NMDAR signaling. These findings underscore the necessity of considering both genetic and lifestyle risk factors in modeling and understanding early late-onset AD pathophysiology. Furthermore, they highlight astrocytic serine biosynthesis as a metabolically sensitive and modifiable pathway with therapeutic relevance. Targeting l- and d-serine metabolism may offer a safer and effective early intervention approach, especially for individuals carrying the APOE-ε4 allele.

Alzheimer’s disease

APOE

Apolipoprotein E

APOE-ɛ4

Apolipoprotein E ɛ4 allele

APP/PS1

Amyloid precursor protein-Presenilin-1

Aβ

Amyloid-beta

CE-LIF

Capillary electrophoresis with laser-induced fluorescence

CNS

Central nervous system

d-ser

d-serine

l-ser

l-serine

fEPSP

Field excitatory postsynaptic potential

HFS

High-frequency stimulation

I/O

Input-output

Knock-in

LTP

Long-term potentiation

NMDAR

N-methyl-D-aspartate receptor

NMDAR-fEPSP

NMDAR-mediated field excitatory postsynaptic potential

PPF

Paired-pulse facilitation

Schaffer collaterals

Western diet

Wild-type.

Funding

This study was funded by INSERM (to P.A., O.S.H.R.); CNRS (to P.A., O.S.H.R.); the Agence Nationale de la Recherche/ EU Joint Programme - Neurodegenerative Disease Research (JPND) (JPND DACAPO-AD: RPB16004GGA) and Vaincre Alzheimer (RAK20002GGA; to O.S.H.R., M.M. and O.A.). This work benefited from the support of various facilities granted by INSERM and LabEX BRAIN ANR-10-LABX-43.

Author Contribution

M.M. performed the experiments, analyzed the data, and drafted the manuscript. O.A., M.I., and L.B.A. assisted with CE-LIF experiments and their analysis. C.P. assisted with additional experiments. H.E. was responsible for mouse breeding and genotyping, and L.D. oversaw animal care. O.S.H.R. and P.A. supervised the project, contributed to data interpretation, and provided manuscript review and editing. All authors reviewed and approved the final version of the manuscript.

Acknowledgement

The authors gratefully acknowledge the staff of the Neurocentre Magendie Animal Facility and the PUMA (Magendie Unified Platforms) for their dedicated support in animal care and experimental logistics. We also thank the technical team in Oliet’s lab for their valuable assistance throughout the project. We are particularly grateful to all past and present members of the Oliet lab for their insightful discussions and continuous support. Finally, we thank the entire JPND DACAPO-AD consortium for all the fruitful and stimulating scientific exchanges.

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No competing interests reported.

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APOE-ε4 Genotype and Western Diet Synergistically Aggravate Synaptic Dysfunction in Alzheimer’s Disease via D-serine Disruption

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Abstract

Figures

Background

Methods

Animals

Diet

Slice preparation

Electrophysiology

Measurement of Amino Acids in Hippocampal Extracellular medium

Drugs and chemicals

Data collection and statistical analyses

Results

Hippocampal Basal Synaptic Transmission Is Impaired in APP/PS1/APOE-ɛ4 Mice

APOE-ɛ4 Genotype Exacerbates Hippocampal Synaptic Plasticity Deficits in APP/PS1 Mice

D-Serine Rescues Impaired NMDAR-Mediated Synaptic Plasticity in APP/PS1/APOE-ɛ4 Mice

Western diet Accelerates Synaptic Plasticity Deficits in APOE-ɛ4-carrier Mice

d-Serine Restores NMDAR-Dependent Synaptic Plasticity From Deficits Present in APOE-ɛ4-carrier Mice on a Western Diet

Discussion

Conclusion

Abbreviations

Declarations

Funding

Author Contribution

Acknowledgement

References

Additional Declarations

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