Alzheimer's disease pathology in APOE transgenic mouse models: The Who, What, When, Where, Why, and How

Abstract

The focus on amyloid plaques and neurofibrillary tangles has yielded no Alzheimer's disease (AD) modifying treatments in the past several decades, despite successful studies in preclinical mouse models. This inconsistency has caused a renewed focus on improving the fidelity and reliability of AD mouse models, with disparate views on how this improvement can be accomplished. However, the interactive effects of the universal biological variables of AD, which include age, APOE genotype, and sex, are often overlooked. Age is the greatest risk factor for AD, while the ε4 allele of the human APOE gene, encoding apolipoprotein E, is the greatest genetic risk factor. Sex is the final universal biological variable of AD, as females develop AD at almost twice the rate of males and, importantly, female sex exacerbates the effects of APOE4 on AD risk and rate of cognitive decline. Therefore, this review evaluates the importance of context for understanding the role of APOE in preclinical mouse models. Specifically, we detail how human AD pathology is mirrored in current transgenic mouse models ("What") and describe the critical need for introducing human APOE into these mouse models ("Who"). We next outline different methods for introducing human APOE into mice ("How") and highlight efforts to develop temporally defined and location-specific human apoE expression models ("When" and "Where"). We conclude with the importance of choosing the human APOE mouse model relevant to the question being addressed, using the selection of transgenic models for testing apoE-targeted therapeutics as an example ("Why").

Keywords: APOE-TR mouse model; APOE4 and AD risk; Alzheimer's Disease (AD); EFAD-Tg mouse model; apoE as a therapeutic target; apolipoprotein E; familial AD transgenic mice (FAD-Tg); sex and AD risk.

Figure 1.. Aβ and tau aggregation.

Two pathways for Aβ and tau monomer aggregation. In the on pathway, protein monomers sequentially aggregate to form larger structures culminating in an amyloid structure, either amyloid plaques for Aβ or NFT for tau. In the off pathway, protein monomers aggregate into oligomers – a persistent, stable, and pathogenic conformation. The upper panel was adapted from Pimplikar (2009); amyloid plaque and NFT staining adapted from Winblad and colleagues (2016).

Figure 2.. Progression of Aβ and tau pathology in humans and Tg mice.

A) Comparison of Aβ pathology progression between AD human patients and FAD-Tg mouse models. B) Comparison of tau pathology progression among AD human patients (Braak staging), FTD human patients, and MAPT-Tg mouse models. The frontal cortex, hippocampus, cerebellum, and brainstem in both human and mouse brain are labeled in leftmost panel in A) to aid in orientation, with additional labels provided to indicate regions affected by pathological progression. Human Aβ and Braak staging panels were adapted from Masters and colleagues (2015). Human FTD was adapted from Wszolek and colleagues (2006). MAPT-Tg mouse pathology was adapted from Sahara and colleagues (2013).

Figure 3.. Therapeutic strategies to target apoE.

Six major categories of apoE-targeted therapeutic candidates in development are ideal for preclinical testing in APOE-Tg mouse models. These include apoE2 overexpression, apoE4 structural correctors, apoE lipidation promoters, apoE inducers, apoE-directed peptides, and antibodies that target various forms of apoE.