Overview and perspective on the therapy of Alzheimer's disease from a preclinical viewpoint.
1. Drugs effective in Alzheimer's disease (AD) should have several aims: to improve the cognitive impairment, control the behavioural and neurological symptoms, delay the progression of the disease, and prevent the onset. In order to attain these targets, cell and animal models are needed on which to test pathogenetic hypothesis and demonstrate the potential effectiveness of new drugs. This overview examines the results obtained in animal models. They are the link between the molecular and biochemical studies on the disease and the reality of human pathology. 2. The development of animal models reproducing the complexity of AD pathogenetic mechanisms and clinical symptoms still represents a challenge for the preclinical investigators. Moreover, the succession of different animal models well documents the progressive widening of our knowledge of the disease with the identification of new therapeutic targets. 3. The main animal models are listed, and their contribution to the understanding of the pathogenic mechanisms and development of the drugs presently used in AD therapy is described. Moreover, their role in the study of future drugs is analysed 4. Preclinical studies on cholinesterases and animal models mimicking the cholinergic hypofunction occurring in AD have been instrumental in developing cholinesterase inhibitors, which are the only recognised drugs for the symptomatic treatment of AD. 5. Artificially created beta-amyloid (A beta) deposits in normal rats, and transgenic mice overexpressing amyloid precursor protein (APP) are the models on which the future treatment are tested. They are aimed to prevent formation of A beta deposits or its transformation in neuritic plaques. 6. Models of brain inflammation, aging animals, and models of brain glucose and energy metabolism impairment make it possible to identify and assess the activity of anti-inflammatory agents, antioxidants, ampakines and other potentially active agents. 7. It is concluded that the present level of information on AD could never have been reached without preclinical studies, and the development of new drugs will always require extensive preclinical investigations.
Pepeu
G
G
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy. pepeu@server1.pharm.unifi.it
D000375:Aging; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1; D016548:Prosencephalon / Q000503:physiopathology; D051381:Rats
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1