Lack of pathology in a triple transgenic mouse model of Alzheimer's disease after overexpression of the anti-apoptotic protein Bcl-2.
Alzheimer's disease (AD) is characterized by the accumulation of plaques containing beta-amyloid (Abeta) and neurofibrillary tangles (NFTs) consisting of modified tau. Although Abeta deposition is thought to precede the formation of NFTs in AD, the molecular steps connecting these two pathologies is not known. Previous studies have suggested that caspase activation plays an important role in promoting the pathology associated with AD. To further understand the contribution of caspases in disease progression, a triple transgenic Alzheimer's mouse model overexpressing the anti-apoptotic protein Bcl-2 was generated. Here we show that overexpression of Bcl-2 limited caspase-9 activation and reduced the caspase cleavage of tau. Moreover, overexpression of Bcl-2 attenuated the processing of APP (amyloid precursor protein) and tau and reduced the number of NFTs and extracellular deposits of Abeta associated with these animals. In addition, overexpression of Bcl-2 in 3xTg-AD mice improved place recognition memory. These findings suggest that the activation of apoptotic pathways may be an early event in AD and contributes to the pathological processes that promote the disease mechanisms underlying AD.
Rohn
Troy T
TT
Department of Biology, Boise State University, Boise, Idaho 83725, USA. trohn@boisestate.edu
Vyas
Veera
V
Hernandez-Estrada
Tatiana
T
Nichol
Kathryn E
KE
Christie
Lori-Ann
LA
Head
Elizabeth
E
D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000682:Amyloid / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000503:physiopathology; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009930:Organic Chemicals; D053764:Presenilin-1 / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D005452:Fluoresceins; D009930:Organic Chemicals; D053764:Presenilin-1; D019253:Proto-Oncogene Proteins c-bcl-2; C435731:fluoro jade; D016875:tau Proteins; D020169:Caspases