APP mouse models for Alzheimer's disease preclinical studies

Abstract

Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

“…Lack of Congo red staining suggested that degree of amyloid accumulation is not as high in this Sgo1 −/+ model as existing EOAD mouse models that typically express a few‐to‐several‐fold amount of total amyloids compared with controls and show Congo red staining (Kitazawa et al., 2012; Onos et al., 2016; Sasaguri et al., 2016). The result was in agreement with immunoblots in Figure 1 indicating only mild increase in total amyloids (amyloid‐β and APP combined) in Sgo1 −/+ compared with age‐matched wild type and BubR1 −/+ .…”

“…Major pathological features of the human AD brain include plaques of amyloid‐β made of cleaved APP, tangles of Tau proteins, and congophilic cerebral amyloid angiopathy (Kitazawa, Medeiros, & Laferl, 2012; Onos, Sukoff Rizzo, Howell, & Sasner, 2016; Sasaguri et al., 2016; Scheltens et al., 2016). With insufficient knowledge on the cause, modeling LOAD in rodents has been an issue.…”

“…Normally, mice do not develop AD, which has been interpreted as due to their shorter lifespan and sequence differences in APP and Tau. Various transgenic mouse models with modified APP, Tau, and others have been developed for EOAD (Kitazawa et al., 2012; Onos et al., 2016; Sasaguri et al., 2016). However, LOAD models are limited to apes and are practically nonexistent in rodents.…”

Endoplasmic reticulum stress responses in mouse models of Alzheimer's disease: Overexpression paradigm versus knockin paradigm

“…The App-KI mice, which express humanized A with familial AD mutations at endogenous levels, exhibit AD-associated pathologies including pronounced A amyloidosis and gliosis (3) (4). In contrast, App-KI failed to reproduce some of the observations made using conventional mouse models (3)(4)(5) …”

Novel Quantitative Analyses of Spontaneous Synaptic Events in Cortical Pyramidal Cells Reveal Subtle Parvalbumin-Expressing Interneuron Dysfunction in a Knock-In Mouse Model of Alzheimer’s Disease

“…Most of the studies on pathologic Aβ and subsequent alterations in synaptic and network activities have been using transgenic mouse models that overproduce mutant hAPP. Although these mouse models simulate several key aspects of human AD (Games et al, 1995; Hsiao et al, 1996; Sturchler-Pierrat et al, 1997; Götz et al, 2004; Cheng et al, 2007; Cissé et al, 2011; Verret et al, 2012), in these animals, Aβ and other APP fragments maybe overproduced and/or ectopically expressed (Chang and Suh, 2005; Mitani et al, 2012; Nicolas and Hassan, 2014; Kerridge et al, 2015; Nhan et al, 2015; Willem et al, 2015; Xia et al, 2016; Sasaguri et al, 2017). The App NL-F mouse model of AD was generated by manipulating the mouse App gene using a knock-in strategy (Nilsson et al, 2014; Saito et al, 2014), and this new mouse model is expected to advance our understanding of AD pathology.…”