A case for a non-transgenic animal model of Alzheimer's disease.
Alzheimer's disease (AD) is associated with an early impairment in memory and is the major cause of dementia in the elderly. beta-Amyloid (Abeta) is believed to be a primary factor in the pathogenic pathway leading to dementia. Mounting evidence suggests that this syndrome begins with subtle alterations in synaptic efficacy prior to extensive neuronal degeneration and that the synaptic dysfunction could be caused by diffusible oligomeric assemblies of Abeta. This paper reviews the findings from behavioral analysis, electrophysiology, neuropathology and nootropic drug screening studies involving exogenous administration of Abeta in normal rodent brains. This non-transgenic model of amyloid pathology in vivo is presented as a complementary alternative model to transgenic mice to study the cellular and molecular pathways induced by amyloid, which in turn may be a causal factor in the disruption of cognition. The data reviewed here confirm that the diffusible form of Abeta rapidly induces synaptic dysfunction and a secondary process involving cellular cascades induced by the fibrillar form of amyloid. The time-course of alteration in memory processes implicates at least two different mechanisms that may be targeted with selective therapies aimed at improving memory in some AD patients.
Stéphan
A
A
Department of Psychiatry and the Brain Research Centre, University of British Columbia, Vancouver, Canada. astephan@interchange.ubc.ca
Phillips
A G
AG
D000544:Alzheimer Disease / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology*; D004195:Disease Models, Animal; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008845:Microinjections; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D018697:Nootropic Agents / Q000627:therapeutic use; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018697:Nootropic Agents