APP transgenic mouse models and their use in drug discovery to evaluate amyloid- lowering therapeutics.
A critical requirement in the development of Alzheimer's disease (AD) therapeutics is a demonstration of the in vivo efficacy of compounds in pre-clinical disease relevant models. One of the most frequently used models in AD research are transgenic mice overexpressing mutant forms of human amyloid precursor protein (APP) that are associated with early-onset familial AD. These mice exhibit an age-dependent accumulation and deposition of amyloid -peptide (A) as extracellular plaques in the brain, and thereby depict one of the key pathologies observed in the brains of AD patients. Although these mouse models do not recapitulate all the pathological features of AD, they have been invaluable in the development of therapeutic agents aimed at lowering A production, inhibiting A deposition or facilitating A clearance. Further development of these APP transgenic models led to the incorporation of transgenes for human mutant presenilins, resulting in an accelerated A deposition rate and human mutant tau protein leading to neurofibrillary tangle-like pathology. The latter was a major advance in the development of AD models, as it allowed researchers to investigate the interplay between the two key pathologies of AD. This review highlights how APP transgenic mouse models have successfully been used in drug discovery to support the progression of A lowering therapeutics to clinical trials to ultimately test the 'amyloid hypothesis' of AD.
Hussain
Ishrut
I
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Ltd, New Frontiers Science Park, Harlow, Essex, UK. ishrut.2.hussain@gsk.com
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism; D058225:Plaque, Amyloid / Q000187:drug effects / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases