Animal models of Alzheimer's disease: Current strategies and new directions

Abstract

Animal models constructed using pathogenic factors have significantly advanced drug development for Alzheimer's disease (AD). These predominantly transgenic models, mainly in mice, replicate pathological phenotypes through gene mutations associated with familial AD cases, thus serving as vital tools for assessing drug efficacy and for performing mechanistic studies. However, the species-specific differences and complex, heterogeneous nature of AD etiology pose considerable challenges for the translatability of these animal models, limiting their utility in drug development. This review offers a comprehensive analysis of widely employed rodent (mice and rats) and non-rodent models ( Danio rerio (zebrafish), Drosophila melanogaster, and Caenorhabditis elegans), detailing their phenotypic features and specific research applications. This review also examines the limitations inherent in these models and introduces various strategies for expanding AD modeling across diverse species, emphasizing recent advancement in non-human primates (NHPs) as valuable models. Furthermore, potential insights from the integration of innovative technologies in AD research are discussed, while providing valuable perspectives on the future development of AD animal models.

Keywords: Alzheimer’s disease; Animal models; Aβ; Non-human primates; Tau.

Figure 1

Main pathogenic mutation sites and related secretase sites in FAD associated with APP and PSEN1 and FTD associated with MAPT A: APP isoforms containing 751 or 695 amino acids with main pathogenic mutations, as well as primary secretase cleavage sites: In healthy individuals, α-secretase cleaves APP, producing soluble APP; in disease states, β-secretase and γ-secretase abnormally cleave APP in sequence, initially forming the Aβ peptide fragment. B: Full-length PSEN1 fragments and fragments with exon 9 deletion, as well as main pathogenic mutations. C: Tau 4R1N isoform and its main pathogenic mutations. APP: Amyloid precursor protein; MAPT: Microtubule-associated protein tau; PSEN1: Presenilin-1; FAD: Familial Alzheimer’s disease; FTD: Frontotemporal dementia.

Figure 2

Formation of CTF-β and antibody epitopes A: After cleavage by β-secretase, APP forms the sAPPβ peptide (extracellular segment of APP in the generation of Aβ) and CTF-β peptide (intracellular segment of APP in the generation of Aβ). B: Correspondence between CTF-β and targets of major pipeline drugs aimed at amyloid plaques, showing that CTF-β can bind to all therapeutic anti-Aβ antibodies (https://clinicaltrials.gov/). APP: Amyloid precursor protein; AICD: APP intracellular domain; sAPPβ: Soluble peptide APPβ; CTF-β: Carboxy-terminal fragment β.

Figure 3

Timeline of pathological progression in AD transgenic mouse models with reference to human age Timeline illustrates age at which various pathological features emerge in different transgenic mouse models for AD. Specific transgenic models (Tg2576, APP23, APPswe/PSEN1dE9, 5xFAD, 3xTg, PS19, rTg4510, APP knock-in mice) are listed for clarity. Mouse Age (Months) vs. Human Age (Approximate Correspondence) ( Vermunt et al., 2019) (Preclinical & Prodromal AD; Mild AD dementia; Moderate AD dementia) ( Johnson et al., 2023).

Figure 4

Modeling strategies/mutation sites and main phenotypes of principal model organisms used in AD research Principal model organisms include Caenorhabditis elegans, Danio rerio (Zebrafish), Drosophila melanogaster, Mus musculus (mice), Rattus norvegicus (rats), Tupaia belangeri chinensis (Chinese tree shrews), and Macaca mulatta (macaques). BACE1: beta-secretase 1; UTR: untranslated regions; FTDP-17: frontotemporal dementia with Parkinsonism-17; NFT: neurofibrillary tangle; TREM2: triggering receptor expressed in myeloid cells 2; PSEN1: presenilin 1.