Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer’s disease and apoE TR mouse cortex

Abstract

The apolipoprotein E4 allele (APOE4) contributes to Alzheimer’s disease (AD) risk and APOE2 is protective, but the relevant cellular mechanisms are unknown. We have used flow cytometry analysis to measure apolipoprotein E (apoE) and amyloid beta peptide (Aβ) levels in large populations of synaptic terminals from AD and aged cognitively normal controls, and demonstrate that modest but significant increases in soluble apoE levels accompany elevated Aβ in AD cortical synapses and in an APP/PS1 rat model of AD. Dual labeling experiments document co-localization of apoE and Aβ in individual synapses with concentration of Aβ in a small population of apoE-positive synapses in both AD and controls. Consistent with a clearance role, the apoE level was higher in Aβ-positive synapses in control cases. In aged targeted replacement mice expressing human apoE, apoE2/4 synaptic terminals demonstrated the highest level of apoE and the lowest level of Aβ compared to apoE3/3 and apoE4/4 lines. In apoE2/4 terminals, the pattern of immunolabeling for apoE and Aβ closely resembled the pattern in human control cases, and elevated apoE was accompanied by elevated free cholesterol in apoE2/4 synaptic terminals. These results are consistent with a role for APOE in Aβ clearance in AD synapses, and suggest that optimal lipidation of apoE2 compared to E3 and E4 makes an important contribution to Aβ clearance and synaptic function.

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

“…People who carry APOE ε4 allele have an increased risk of developing AD, while APOE ε2 carriers are protected from the disease (Deelen et al ., 2011). The level of soluble ApoE protein increases both in patients with AD and in APP/PS1 rat model of AD (Arold et al ., 2012). It plays an important role in Aβ aggregation and fibril formation (Wisniewski et al ., 1994).…”

Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*

“…At the synapse, as with the whole brain, apoE/A␤ appears to be present as an insoluble and soluble form. IHC co-localization of apoE and A␤ at the synapse is a measure of primarily insoluble apoE/A␤ (35,36), and data demonstrate insoluble apoE/A␤ appears to form preferentially with apoE4 compared with apoE3 (36). Previous results have shown that the detergent and guanidine extraction pattern of mouse apoE parallels that of A␤42 in 5ϫFAD mice (5), and the proportion of apoE/A␤ in insoluble fractions was increased in AD synaptosomes compared with controls.…”

“…ApoE/A␤ complex has been detected in the soluble fraction of human brain (33) and in human cerebrospinal fluid (CSF) (30,34), although the data were primarily produced using Western analysis of SDS-PAGE. By IHC, apoE also co-localizes with A␤ at the synapse (35), and insoluble apoE/A␤ complexes appear to form preferentially with apoE4 compared with apoE3 (36). However, the effect of the APOE genotype on soluble synaptic apoE/A␤ levels remains unclear (37)(38)(39)(40).…”

Direct Transcriptional Effects of Apolipoprotein E

“…Human ApoE3 and ApoE4 transgenic mice (driven by the human APOE promoter) were made in the ApoE-ko background (Xu et al, 1996;Sullivan et al, 1997;Holtzman et al, 1999;Teter et al, 2002;Arold et al, 2012). These mice show equivalent levels of ApoE expression in astrocytes, microglia, and neurons and maintain the human pattern of regulation and regional expression (Xu et al, 1996).…”