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Accelerating Alzheimer's research through ‘natural’ animal models

Braidy, Nadya; Poljak, Annea,b,c; Jayasena, Tharushaa; Mansour, Husseina; Inestrosa, Nibaldo C.d; Sachdev, Perminder S.a,e

Current Opinion in Psychiatry: March 2015 - Volume 28 - Issue 2 - p 155–164
doi: 10.1097/YCO.0000000000000137
NEUROCOGNITIVE DISORDERS: Edited by Perminder S. Sachdev

Purpose of review Alzheimer's disease is a complex multifactorial age-related neurodegenerative disorder. Current transgenic animal models do not fully recapitulate human Alzheimer's disease at the molecular, cellular and behavioural levels. This review aims to address the clinical relevance of using ‘physiologically’ aged rats, dogs and Octodon degus, as more representative ‘natural’ ecologically valid models to elucidate mechanistic aspects of Alzheimer's disease, and for the development of therapeutic agents to attenuate age-related cognitive decline.

Recent findings Aged rats, dogs and O. degus decline cognitively and ultimately develop Alzheimer's disease-like symptoms in response to the natural ageing process. Aged rats provide a tractable and popular model to examine the neurobiological basis underlying cognitive decline with age, but they do not develop Alzheimer's disease pathology. Progressive accumulation of abnormal amyloid-beta in extracellular plaques and surrounding cerebral vasculature is a common feature in human Alzheimer's disease, aged canine model and most nonhuman primates. Interestingly, the O. degus develops amyloid-beta deposits, neurofibrillary tangles containing hyperphosphorylated tau protein, altered cholinergic transmission and cognitive deficits analogous to those observed in Alzheimer's disease. Natural animal models better represent the full pathophysiology of Alzheimer's disease and are not only a viable alternative to transgenic models, but also are arguably the preferable model.

Summary ‘Natural’ models are useful to elucidate the neurobiological basis of Alzheimer's disease and develop effective therapeutic strategies that can be translated into human clinical trials.

aCentre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales

bSchool of Medical Sciences, University of New South Wales

cBioanalytical Mass Spectrophotometry Facility, University of New South Wales, Sydney, New South Wales, Australia

dFaculty of Biological Sciences, Centre for Ageing and Regeneration (CARE), P. Catholic University of Chile, Santiago, Republic of Chile

eNeuropsychiatric Institute, Prince of Wales Hospital, Sydney, New South Wales, Australia

Correspondence to Perminder S. Sachdev, Professor, UNSW School of Psychiatry, NPI, Euroa Centre, Prince of Wales Hospital, Barker Street, Randwick, NSW 2031, Australia. Tel: +61 2 9382 3763; fax: +61 2 9382 3774; e-mail:

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