Caspase-cleaved amyloid precursor protein in Alzheimer's disease.
Caspase-3 mediated cleavage of the amyloid precursor protein (APP) has been proposed as a putative mechanism underlying amyloidosis and neuronal cell death in Alzheimer's disease (AD). We utilized an antibody that selectively recognizes the neo epitope generated by caspase-3 mediated cleavage of APP (alphadeltaC(csp)-APP) to determine if this proteolytic event occurs in senile plaques in the inferior frontal gyrus and superior temporal gyrus of autopsied AD and age-matched control brains. Consistent with a role for caspase-3 activation in AD pathology, alphadeltaC(csp)-APP immunoreactivity colocalized with a subset of TUNEL-positive pyramidal neurons in AD brains. AlphadeltaC(csp)-APP immunoreactivity was found in neurons and glial cells, as well as in small- and medium-size particulate elements, resembling dystrophic terminals and condensed nuclei, respectively, in AD and age-matched control brains. There were a larger number of alphadeltaC(csp)-APP immunoreactive elements in the inferior frontal gyrus and superior temporal gyrus of subjects with AD pathology than age-matched controls. AlphadeltaC(csp)-APP immunoreactivity in small and medium size particulate elements were the main component colocalized with 30% of senile plaques in the inferior frontal gyrus and superior temporal gyrus of AD brains. In some control brains, alphadeltaC(csp)-APP immunoreactivity appeared to be associated with a clinical history of metabolic encephalopathy. Our results suggest that apoptosis contributes to cell death resulting from amyloidosis and plaque deposition in AD.
Ayala-Grosso
Carlos
C
Department of Pharmacology, McGill University, Montreal, Canada.
Ng
Gordon
G
Roy
Sophie
S
Robertson
George S
GS
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002452:Cell Count; D002540:Cerebral Cortex / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D000939:Epitopes / Q000276:immunology; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009457:Neuroglia / Q000201:enzymology / Q000473:pathology; D058225:Plaque, Amyloid / Q000201:enzymology* / Q000473:pathology; D017966:Pyramidal Cells / Q000201:enzymology / Q000473:pathology; D013702:Temporal Lobe / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation / Q000276:immunology
D016564:Amyloid beta-Protein Precursor; D000939:Epitopes; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases