Can mouse models mimic sporadic Alzheimer's disease?

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia worldwide. As age is the main risk factor, > 97% of all AD cases are of sporadic origin, potentiated by various risk factors associated with life style and starting at an age > 60 years. Only < 3% of AD cases are of genetic origin caused by mutations in the amyloid precursor protein or Presenilins 1 or 2, and symptoms already start at an age < 30 years. In order to study progression of AD, as well as therapeutic strategies, mouse models are state-of-the-art. So far many transgenic mouse models have been developed and used, with mutations in the APP or presenilin or combinations (3×Tg, 5×Tg). However, such transgenic mouse models more likely mimic the genetic form of AD and no information can be given how sporadic forms develop. Several risk genes, such as Apolipoprotein E4 and TREM-2 enhance the risk of sporadic AD, but also many risk factors associated with life style (e.g., diabetes, hypercholesterolemia, stress) may play a role. In this review we discuss the current situation regarding AD mouse models, and the problems to develop a sporadic mouse model of AD.

Keywords: Alzheimer’s disease; beta-amyloid; cerebral amyloid angiopathy; cognitive impairment; sporadic and genetic mouse models; tau; vascular risk factors.

Figure 1

Alzheimer’s disease (AD) is a severe neurodegenerative disorder, characterized by extracellular beta-amyloid plaques (PLQ), intraneuronal tau pathology with formation of neurofibrillary tangles (NFT), vascular dysfunction, inflammation and microglial dysfunction, reactive astrogliosis and cell death of cholinergic neurons. AD can be distinguished into a genetic (< 3% of patients affected) and sporadic (majority of > 97% of all cases) form of the disease. In genetic AD the major risk genes amyloid precursor protein (APP) and presenilin 1&2 (PSEN1&2) are mutated. Transgenic mouse models with mutations in these genes have been developed and allow to study the progression of beta-amyloid and tau pathologies. Age (> 60 years) is the main risk factor to develop sporadic AD, and two risk factors (Apoliprotein E4 and TREM-2) increase the risk, and many risk factors associated with life style play a role in progression. However, so far, the initial causes for sporadic AD are not known and no mouse model for sporadic AD is available. In addition, also other forms of dementia with cognitive impairment have been reported, showing partial overlap with AD, such as cerebral amyloid angiopathy (CAA), vascular dementia (vaD) or pure tauopathies (such as frontotemporal lobe dementia).