Mouse models of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, affecting 35 million people today. The search for new treatments is made ever more urgent by prospects for increasing prevalence due to population aging. Mouse models are one of the most important research tools for finding new treatments for AD. Here, we review those models. We begin by briefly reviewing the AD genetics on which mouse models are based and then consider the most common mouse models of AD, including mice transgenic for human amyloid precursor protein (hAPP) and beta-amyloid (Aβ), mice expressing mutant presenilin genes, mice modeling tau's role in AD, and apolipoprotein E models. The discussion highlights key features and important differences between these mouse models. We conclude with a discussion about the role of AD mouse models in the translational pipeline.

Fig. 1

APP processing and APP mutations. Aβ42 is encoded by amino acids 672–713 of APP (numbered according to the longest isoform, APP770). Aβ is produced through sequential cleavage by β-secretase, then γ-secretase. γ-secretase can cleave at alternate sites to produce Aβ40 or Aβ42. Alternative APP processing by α-secretase prevents Aβ production. Common APP mutations include the Swedish mutation at the β-secretase cleavage site and multiple named and unnamed mutations at the γ-secretase cleavage site. Intra-Aβ mutations are also shown.

Fig. 2

Alternatively spliced isoforms of APP. The APP gene contains 19 exons. Exon 13a is not included in brain isoforms. Exons 7 and 8 can be alternatively spliced to produce APP695, APP751, and APP770. APP751 and APP770 include exon 7 (orange), which encodes a Kunitz protease inhibitor (KPI) domain. APP770 also includes exon 8 (green), which encodes an OX-2 domain.

Fig. 3

Comparison of human and mouse Aβ. Mouse Aβ (mAβ) differs from human Aβ (hAβ) at positions 5, 10, and 13, which affects the aggregation properties of Aβ. β-secretease also has a greater preference for cleavage at the β’ site in mouse Aβ, to produce Aβ_11-x instead of Aβ_1-x.

Fig. 4

Roles for mouse models in the drug discovery pipeline. Mouse models have been very useful in the “basic science” stages of target identification and validation. Mouse models are also used for preclinical testing of lead compounds.