Abstract
This Mini Review discusses the merits and shortfalls of transgenic (tg) rodents modeling aspects of the human Alzheimer’s disease (AD) pathology and their application to evaluate experimental therapeutics. It addresses some of the differences between mouse and rat tg models for these investigations. It relates, in a condensed fashion, the experience of our research laboratory with the application of anti-inflammatory compounds and S-adenosylmethionine (SAM) at the earliest stages of AD-like amyloid pathology in tg mice. The application of SAM was intended to revert the global brain DNA hypomethylation unleashed by the intraneuronal accumulation of amyloid-β-immunoreactive material, an intervention that restored levels of DNA methylation including of the bace1 gene. This review also summarizes experimental pharmacology observations made in the McGill tg rat model of AD-like pathology by applying “nano-lithium” or a drug with allosteric M1 muscarinic and sigma 1 receptor agonistic properties (AF710B). Extremely low doses of lithium (up to 400 times lower than used in the clinic) had remarkable beneficial effects on lowering pathology and improving cognitive functions in tg rats. Likewise, AF710B treatment, even at advanced stages of the pathology, displayed remarkable beneficial effects. This drug, in experimental conditions, demonstrated possible “disease-modifying” properties as pathology was frankly diminished and cognition improved after a month of “wash-out” period. The Mini-Review ends with a discussion on the predictive value of similar experimental pharmacological interventions in current rodent tg models. It comments on the validity of some of these approaches for early interventions at preclinical stages of AD, interventions which may be envisioned once definitive diagnosis of AD before clinical presentation is made possible.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia in the elderly (Hardy et al, 2014; Aisen et al, 2017)
Three of the four drugs approved by the Food and Drug Administration (FDA) for AD are cholinesterase inhibitors (AChEI)
We will provide a concise overview of transgenic rodent models mimicking key aspects of the AD pathology and discuss their value in the drug development pipeline, as well as the challenges to predict drug efficacy in AD patients based on animal studies
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia in the elderly (Hardy et al, 2014; Aisen et al, 2017). We will provide a concise overview of transgenic (tg) rodent models mimicking key aspects of the AD pathology and discuss their value in the drug development pipeline, as well as the challenges to predict drug efficacy in AD patients based on animal studies.
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