An Update of Animal Models of Alzheimer Disease with a Reevaluation of Plaque Depositions

Abstract

Animal models of Alzheimer disease (AD) are used to study the mechanisms underlying AD pathogenesis, genetic interactions with genes of interest, and environmental risk factors that cause sporadic AD as well as to test the therapeutic effects of AD drug-candidates on neuropathology and cognitive function. To attain a comparative view on the AD models developed, representative AD lines were selected and summarized with respect to transgenic constructs and AD-related pathology. In addition, age-dependent plaque deposition data available in the literature for six representative AD models such as Tg2576, PDAPP, TgAPP23, Tg-APPswe/PS1dE9, 3xTg-AD, and 5XFAD mice were reevaluated using a photographic plaque reference scale method that was introduced recently. Tg2576, PDAPP, and TgAPP23 mice, which carry the amyloid precursor protein (APP) transgene, produced initially slow, but progressively accelerated plaque deposition as they aged, resulting in logistic plaque deposition. In contrast, Tg-APPswe/PS1dE9 and 3xTg-AD mice, which carry both APP and PS1 transgenes, developed abruptly accelerated plaque formation from the beginning, resulting in logarithmic plaque deposition. 5XFAD mice, which also carry both the APP and PS1 transgenes, developed a logarithmic deposition beginning at 2 months. This comparative analysis suggests that AD models may be classified into two distinct plaque deposition groups, and that early plaque models such as APPswe/PS1dE9, 3xTg-AD and 5XFAD might be useful to study the biochemical aspects of APP metabolism, whereas late plaque models such as Tg2576, PDAPP, and TgAPP23 might be useful to study more physiological and environmental aspects of AD pathogenesis, which occur on a longer time scale.

Maysin and Its Flavonoid Derivative from Centipedegrass Attenuates Amyloid Plaques by Inducting Humoral Immune Response with Th2 Skewed Cytokine Response in the Tg (APPswe, PS1dE9) Alzheimer’s Mouse Model

“…It was also projected the genetic cause of Alzheimer disease (AD) is understood for less than 1% gene mutations (APP, PS1, PS2) in early onset FAD or 20% (APOE4 allele) in late onset FAD cases, respectively [31]. For the remainder of AD sufferers, multiple genetic and environmental factors probably play a role in contributing to disease onset, severity and progression due to promotion of amyloid-beta peptide (Aβ42/40) generation following proceeding of APP cleavage due to secretase activation [32–34]. To date, there is no cure for AD and therapeutic measures are being actively explored through small molecule likely inhibitors to three isoform of secretases and/or neutralization of amyloid-beta peptide (Aβ42/40) toxicity using biologicals, small molecules, and immunotherapy in the pharmacological active natural compounds.…”

Entorhinal cortical defects in Tg2576 mice are present as early as 2–4 months of age

“…In previous studies, it has been suggested that Tg2576 mice exhibited deficits in tests of spatial memory after 6 months of age (Hsiao, et al, 1996; King, et al, 1999; Westerman, et al, 2002), when β-amyloid plaques becomes prominent (Hsiao, et al, 1996; Lee and Han, 2013). Our results suggest that when a task of spatial memory is used that is dependent on the EC, such as OP, impairments can be detected earlier.…”

“…To gain insight into these questions, we used the Tg2576 mouse model of AD neuropathology. The Tg2576 mouse uses the hamster prion promoter to overexpress human amyloid precursor protein (hAPP) 695 with the mutation of a Swedish family with AD (K670N/M671L), and progressive Aβ pathology occurs after 6 months of age (Hsiao, et al, 1996; Irizarry, et al, 1997; Kawarabayashi, et al, 2001; Lee and Han, 2013; Westerman, et al, 2002). …”

Positive and negative early life experiences differentially modulate long term survival and amyloid protein levels in a mouse model of Alzheimer's disease

“…Chronic stress in adulthood e.g. elevates Aβ 40 and Aβ 42 brain levels, accelerates amyloid plaque formation, increases tauopathy and neuronal atrophy, and impairs learning and memory in various mouse models [11–13]. …”