Rodent Models of Alzheimer's Disease: Past Misconceptions and Future Prospects

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective treatments, not least due to the lack of authentic animal models. Typically, rodent models recapitulate the effects but not causes of AD, such as cholinergic neuron loss: lesioning of cholinergic neurons mimics the cognitive decline reminiscent of AD but not its neuropathology. Alternative models rely on the overexpression of genes associated with familial AD, such as amyloid precursor protein, or have genetically amplified expression of mutant tau. Yet transgenic rodent models poorly replicate the neuropathogenesis and protein overexpression patterns of sporadic AD. Seeding rodents with amyloid or tau facilitates the formation of these pathologies but cannot account for their initial accumulation. Intracerebral infusion of proinflammatory agents offer an alternative model, but these fail to replicate the cause of AD. A novel model is therefore needed, perhaps similar to those used for Parkinson's disease, namely adult wildtype rodents with neuron-specific (dopaminergic) lesions within the same vulnerable brainstem nuclei, 'the isodendritic core', which are the first to degenerate in AD. Site-selective targeting of these nuclei in adult rodents may recapitulate the initial neurodegenerative processes in AD to faithfully mimic its pathogenesis and progression, ultimately leading to presymptomatic biomarkers and preventative therapies.

Keywords: Alzheimer’s disease; Parkinson’s disease; animal models; isodendritic core; mice; rats.

Figure 1

A novel animal model of AD. Schematic of the isodendritic core (IC) in the human brain, highlighting the main cholinergic, serotonergic, dopaminergic and noradrenergic nuclei (A). The structure and sequence of T14 at the C-terminus of acetylcholinesterase (AChE) (B). Proposed mechanisms of delivery of T14 to the IC in laboratory rodents, either via direct infusion of the peptide or the viral overexpression of exon 6 of AChE (which encodes T14), into the target nuclei (C). Schematic of the hypothesised effects of T14 administration into the rodent brain, including amyloid beta (Aβ) and neurofibrillary tau tangles (NFTs), mimicking AD progression, based on data published in [217,218] (D). Figures made using BioRender.