Endogenous Apolipoprotein E (ApoE) Fragmentation Is Linked to Amyloid Pathology in Transgenic Mouse Models of Alzheimer’s Disease

Abstract

The epsilon 4 allele of the apolipoprotein E (ApoE4) gene is the most important risk factor implicated in Alzheimer's disease (AD) etiology. ApoE4 is more susceptible to proteolysis, and ApoE fragments have been shown to promote tau hyperphosphorylation and exert neurotoxic properties. While a plethora of studies deals with the effect of ApoE and its fragments on amyloid-β peptide (Aβ) deposition and clearance, it is largely unknown whether Aβ in turn influences human or murine ApoE expression and its proteolysis. The present study is the first to show that endogenous murine ApoE becomes proteolytically processed in a way reminiscent of human ApoE fragmentation in different AD mouse models, including APP/PS1KI or 5XFAD. Murine ApoE fragments were demonstrated to accumulate mainly in synaptic fractions in AD mouse models. In vitro experiments, as well as analysis of mouse models at different time points, suggest that the amount of total ApoE is associated with extracellular Aβ while the amount of its fragments is linked to intracellular Aβ levels. Murine ApoE fragmentation is a common feature in different AD transgenic mouse models and could be directly associated with intraneuronal Aβ accumulation. Extracellular amyloid induces an elevation in full-length ApoE expression, which might present a protective mechanism toward Aβ clearance. The demonstrated fragments of murine ApoE in vitro and in vivo might therefore play a crucial role in the progression of AD pathology in murine AD models.

Phagocytosis of Apoptotic Cells Is Specifically Upregulated in ApoE4 Expressing Microglia in vitro

“…They could show that neuronal ApoE, especially ApoE4, is undergoing proteolytic processing which result in C-terminal truncated fragments that cause cytoskeletal changes (Huang and Mahley, 2014). Moreover, it could be shown that intracellular ApoE fragmentation is especially linked to amyloid pathology as in brains of AD mouse models and patients with AD (Huang et al, 2001; Saul and Wirths, 2017). Alternatively, Theendakara et al (2016) demonstrated that ApoE might also function as a transcription factor in neurons.…”

Apolipoprotein E Deficiency Exacerbates Spinal Cord Injury in Mice: Inflammatory Response and Oxidative Stress Mediated by NF-κB Signaling Pathway

“…APOE plays a crucial role in modulating neuronal repair, remodeling, and protection after CNS trauma and disease (Yin et al, 2012 ; Saul and Wirths, 2017 ; Teng et al, 2017 ). During nerve regeneration, APOE is involved in the mobilization and reutilization of myelin-derived cholesterol for axon repair (Mahley, 1988 ; Li et al, 2010 ).…”

EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerʼns disease

“…Decreases in presynaptic and postsynaptic proteins in HP and CX contribute to altered functional connectivity, suggesting (67,348,349); TBSX-apoE: in TBSX extraction fraction by ELISA (67). APP processing: APP, BACE, C-terminal fragments by Western blot (49,52,53,58,67,222,329,336,337,339,(348)(349)(350)(351)(352). Neurotrophic factors: brain-derived neurotrophic factor (BDNF) and pCREB proteins by Western blot or mRNA by qPCR (55,61,336,350,352,353).…”