Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer's disease

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Dementia is a term used to describe a syndrome, caused by various diseases of the brain, characterized by significant decline in multiple cognitive areas including memory, language, social cognition, executive and perceptual functions. The most recent Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM–V) introduces the term ‘Major Neurocognitive Disorders’, with some changes in criteria compared to DSM–IV 1, including more specific details on the degree of impairment observed in the aforementioned cognitive domains, and the inability to explain such impairments by any other means 2. Population‐based studies show that Alzheimer's disease (AD), dementia with Lewy bodies and vascular dementia are the most common pathological substrates for dementia 3. AD is the most common type of dementia and is associated with a decline in cognitive abilities, such as memory and visuo‐spatial skills. Early‐onset familial AD accounts for <1% of AD diagnoses, and typically occurs before the age of 65 years 7. Late‐onset AD most often occurs over the age of 65 years and is much more common.
Murine models of AD recapitulate aspects of the disease, often through gene mutations associated with familial AD, and can powerfully elucidate critical aspects of pathogenesis. Although this type of AD is less common, the pathological phenotypes are similar to sporadic AD. Extracellular beta amyloid plaques, intracellular hyperphosphorylated tau, synaptic and neuronal loss and neuroinflammation, are all associated with the disease 8. The amyloid cascade hypothesis 9 proposed that amyloid (Aβ) plaque deposition is key to the pathogenesis of AD, with tau pathology, inflammation and subsequent cell damage as contributing factors. Neuronal and neurotransmitter changes follow Aβ deposition, leading eventually to cell death. Cognitive decline may be a result of neuronal dysfunction from toxic soluble Aβ 11, or inhibited synapse remodelling linked to Aβ oligomers 12. Therapeutic trials have targeted the clearance of Aβ, with some success in both murine models 13 and in humans 15. However, immunotherapy targeting Aβ has not yet translated into improved cognitive functioning 17. A greater understanding of the role of Aβ molecular forms, their temporal role in AD development and their interaction with other pathogenic factors is required.
Oxidative stress is a key factor in AD, whereby the balance between oxidants and antioxidants is disrupted, leading to an excess of oxidants 20. Several mechanisms may contribute towards oxidative stress, including dysfunction of mitochondria 22, accumulation of Aβ 22 and hyperphosphorylated tau 25 and neuroinflammation 27. Biomarkers of oxidative stress in AD have been identified; however, a relatively recent systematic review by Chang et al. 29 concluded that although serum markers of lipid peroxidation are elevated in AD, there is insufficient evidence to justify the use of biomarkers as predictors of AD severity or outcome.
Recent studies have investigated the interacting and modifying factors of the defining pathological features of AD; Jonsson et al. 30 reported that a coding mutation (A673T) in the amyloid precursor protein (APP) gene has a protective effect against AD and cognitive decline. Genome‐wide association studies have reported AD genetic risk factors, with Chapuis et al. 31 recently identifying a gene (FERMT2) that has a role in regulating APP metabolism and Aβ production. Researchers are yet to fully explore the interacting and modifying factors of AD pathogenesis using AD mouse models in great detail.
The current review will discuss how well, and in what aspects, murine models of AD recapitulate the physiological, neuropathological and cognitive changes associated with human AD.

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