C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-β (Aβ) and acts in concert with Aβ to elicit neuronal and behavioral deficits in mice

Abstract

Apolipoprotein (apo) E4 is the major known genetic risk factor for Alzheimer's disease (AD). We have shown in vitro and in vivo that apoE4 preferentially undergoes aberrant cleavage in neurons, yielding neurotoxic C-terminal-truncated fragments. To study the effect of these fragments on amyloid-β (Aβ) clearance/deposition and their potential synergy with Aβ in eliciting neuronal and behavioral deficits, we cross-bred transgenic mice expressing apoE3, apoE4, or apoE4(Δ272-299) with mice expressing human amyloid protein precursor (APP) harboring familial AD mutations (hAPP FAD ). At 6-8 mo of age, hAPP FAD mice expressing apoE3 or apoE4 had lower levels of hippocampal Aβ (94% and 89%, respectively) and less Aβ deposition (89% and 87%) than hAPP FAD mice without apoE, whereas hAPP FAD mice expressing mouse apoE had higher Aβ levels. Thus, human apoE stimulates Aβ clearance, but mouse apoE does not. Expression of apoE4(Δ272-299) reduced total Aβ levels by only 63% and Aβ deposition by 46% compared with hAPP FAD mice without apoE. Unlike apoE3 and apoE4, the C-terminaltruncated apoE4 bound poorly with Aβ peptides, leading to decreased Aβ clearance and increased Aβ deposition. Despite their lower levels of Aβ and Aβ deposition, hAPP FAD /apoE4(Δ272-299) mice accumulated pathogenic Aβ oligomers and displayed neuronal and behavioral deficits similar to or more severe than those in hAPP FAD mice. Thus, the C-terminal-truncated apoE4 fragment inefficiently clears Aβ peptides and acts in concert with low levels of Aβ to elicit neuronal and behavioral deficits in mice.animal model | neurodegeneration A lzheimer's disease (AD) is a complex neurodegenerative disorder likely caused by interactions among multiple genetic and environmental factors. Mutations in amyloid protein precursor (APP), presenilin-1 (PS1), and PS2 have been linked to early-onset familial AD (1-3), which accounts for <5% of AD cases. All mutations affect APP processing and alter the production of amyloid-β(Aβ) peptides (1, 2). Several transgenic mouse models have been developed to study the effects of Aβ on neuronal and behavioral deficits (4). The J20 line of transgenic mice expressing human APP harboring familial AD mutations (hAPP FAD ) accumulates neurotoxic Aβ peptides and display synaptic and cognitive deficits at 5-6 mo of age (5-7).Apolipoprotein (apo) E4, one of three isoforms of apoE (apoE2, apoE3, and apoE4), is the major genetic risk factor for late-onset AD, which accounts for >95% of AD cases (8-10). ApoE4 carriers account for 65-80% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis (11). Emerging data suggest that apoE4 contributes to AD by interacting with different pathogenic factors through various pathways (12)(13)(14)(15).Several mouse models have been established to study the roles of apoE4 in AD pathogenesis. Neuron-specific apoE4 transgenic mice (NSE-apoE4) develop neuronal and spatial learning and memory deficits (16-18). Astrocyte-specific apoE4 transgenic mice (GFAP-apoE4) display working memory deficits wit...

Binding of Apolipoprotein E Inhibits the Oligomer Growth of Amyloid-β Peptide in Solution as Determined by Fluorescence Cross-correlation Spectroscopy

“…If such an effect occurs in vivo, it may correlate with a packaging of A␤ to facilitate its clearance from the brain (45). We and others have previously postulated that reduced binding of apoE4 to oligomeric A␤ may correlate with a loss of apoE protection with regard to A␤ clearance (29,(45)(46)(47)(48). The ability of ALEX-FCCS to provide a quantitative measure of apoE binding to A␤ and also A␤ assembly will be helpful in not only elucidating the molecular mechanism of A␤ pathogenicity and protection, but also in identifying factors that influence these processes.…”

Apolipoprotein E Sets the Stage: Response to Injury Triggers Neuropathology

“…Importantly, it is established that there are apoE isoform–specific effects on the Aβ pathway (Huang and Mucke, 2012; Kim et al, 2009; Selkoe, 2011) and that apoE4 expression is associated with a significant increase in amyloid plaques at earlier ages compared with apoE3 or apoE2. Furthermore, apoE4 is known to impair Aβ clearance (Bien-Ly et al, 2011; Castellano et al, 2011; Deane et al, 2008; Kim et al, 2011) and accelerate amyloid synthesis (Ye et al, 2005), as well as amyloid fibril formation and deposition (Bales et al, 1999; Bien-Ly et al, 2011; Sanan et al, 1994; Wisniewski et al, 1995). …”

“…First, can one equate the effect of increasing mouse apoE to that of the human apoE isoforms? Mouse apoE is neither structurally nor functionally equivalent to human apoE3 or apoE4 (Zhong and Weisgraber, 2009) and behaves differently from the human isoforms with respect to Aβ clearance (Bien-Ly et al, 2011). Importantly, it was recently reported that genetically increasing either human apoE3 or apoE4 levels increased Aβ accumulation (Bien-Ly et al, 2012; Kim et al, 2011).…”

“…Alternatively, astrocyte-derived apoE4 might directly damage the integrity of the BBB, allowing blood-derived proteins to enter the brain and injure neurons, and setting up the detrimental response to injury (Akassoglou et al, 2004; Bell et al, 2012). What is not speculative, however, is that astrocytic apoE4 can negatively impact Aβ clearance and/or deposition (Bien-Ly et al, 2011; Castellano et al, 2011; Kim et al, 2011) and thus induce the apoE neurotoxic pathway.…”

Novel Susceptibility Loci for Alzheimer's DXSisease

“…This notion is supported by in vitro studies demonstrating that the APOEε4 isoform binds Aβ peptides more vigorously than APOE ε3 [23] and leads to increased Aβ aggregation [24,25], and by studies demonstrating that knockout APOE −/− mice develop less nonfibrillar Aβ deposits [26,27]. hAPP transgenic mice expressing human APOE3 or APOE4 also demonstrate a gene dose- and isoform-dependent APOE effect on Aβ accumulation [28]. APOE is also an Aβ chaperone involved in Aβ clearance.…”