APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice

Abstract

BackgroundAlzheimer’s disease (AD) causes progressive loss of memory and cognition, exacerbated by APOE4, the greatest genetic risk factor for AD. One proposed mechanism for apolipoprotein E (apoE) effects on cognition is via NMDAR-dependent signaling. APOE genotype-specific effects on this pathway were dissected using EFAD-transgenic (Tg) mice (5xFAD mice, that over-express human amyloid-beta (Aβ) via 5 familial-AD (FAD) mutations, and express human apoE), and 5xFAD/APOE-knockout (KO) mice. Previous data from EFAD-Tg mice demonstrate age-dependent (2-6 months), apoE-specific effects on the development of Aβ pathology. This study tests the hypothesis that apoE4 impairs cognition via modulation of NMDAR-dependent signaling, specifically via a loss of function by comparison of E4FAD mice with 5xFAD/APOE-KO mice, E3FAD and E2FAD mice.ResultsUsing female E2FAD, E3FAD, E4FAD and 5xFAD/APOE-KO mice aged 2-, 4-, and 6-months, the Y-maze and Morris water maze behavioral tests were combined with synaptic protein levels as markers of synaptic viability. The results demonstrate a greater age-induced deficit in cognition and reduction in PSD95, drebrin and NMDAR subunits in the E4FAD and 5xFAD/APOE-KO mice compared with E2FAD and E3FAD mice, consistent with an apoE4 loss of function. Interestingly, for NMDAR-mediated signaling, the levels of p-CaMK-II followed this same apoE-specific pattern as cognition, while the levels of p-CREB and BDNF demonstrate an apoE4 toxic gain of function: E2FAD > E3FAD > 5xFAD/APOE-KO > E4FAD.ConclusionThese findings suggest that compared with E2FAD and E3FAD, E4FAD and 5xFAD/APOE-KO mice exhibit enhanced age-induced reductions in cognition and key synaptic proteins via down-regulation of an NMDAR signaling pathway, consistent with an apoE4 loss of function. However, levels of p-CREB and BDNF, signaling factors common to multiple pathways, suggest a gain of toxic function. Publications in this field present contradictory results as to whether APOE4 imparts a loss or gain of function. As with the results reported herein, the overall effect of APOE4 on a given CNS-specific measure will be the product of multiple overlapping mechanisms. Thus, caution remains critical in determining whether APOE gene inactivation or therapies that correct the loss of positive function related to apoE4, are the appropriate therapeutic response.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0002-2) contains supplementary material, which is available to authorized users.

ApoE4 Accelerates Early Seeding of Amyloid Pathology

“…Consistent with this notion, we showed that astrocytic apoE4 expression enhances plaque-associated inflammatory responses, whereas increased levels of apoE3 suppress Aβ-driven neuroinflammation and ameliorates post-synaptic alteration. In addition, apoE isoforms have been shown to differentially regulate synaptic functions by multiple mechanisms, such as modulating the signaling function of post-synaptic receptors (Chen et al, 2010; Liu et al, 2015b). How expression of astrocytic apoE3 and apoE4 impacts synaptic functions and plasticity in the absence of amyloid pathology requires future investigation.…”

Epidermal growth factor prevents APOE4 and amyloid-beta-induced cognitive and cerebrovascular deficits in female mice

“…Morris water maze (MWM) was conducted as described in [35] with slight modifications in three phases. The circular pool was 120 cm in diameter and 50 cm tall, and the circular escape platform was 10 cm in diameter.…”

Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

“…In animals, reduced excitatory synaptic transmission/dendritic arborisation [74], reduced spine length/density [75, 76], and reduced synaptic markers [63] have been observed in apoE4-TR mice compared to apoE3-TR mice. Enhanced age-dependent cognitive decline in apoE4 accompanied by reduction in postsynaptic density 95 (PSD-95), drebrin and NMDA receptor subunits was also observed in amyloid mouse model when compared to apoE2 or apoE3 [77]. …”