Caspase-3 cleaved spectrin colocalizes with neurofilament-immunoreactive neurons in Alzheimer's disease.
Corticocortical disconnection in Alzheimer's disease occurs by the progressive impairment and eventual loss of a small subset of pyramidal neurons in layers III and V of association areas of the neocortex. These neurons exhibit large somatic size, extensive dendritic arborization and high levels of nonphosphorylated neurofilaments of medium and high molecular weight that can be identified using a monoclonal SMI-32 antibody. It is thought that the accumulation of amyloid Abeta and neurofibrillary tangles may provoke metabolic disturbances that result in the loss of these SMI-32 immunoreactive neurons. The recent detection of increased levels of caspase-3 cleaved fodrin in frontal, temporal and parietal association areas in Alzheimer's disease brains suggests that programmed cell death may contribute to the destruction of SMI-32 positive neurons. In the present study, we utilized an antibody that selectively recognizes the 120 kDa breakdown product of alphaIIspectrin (fodrin) generated by caspase-3 to determine whether this protease is activated in vulnerable pyramidal neurons located in layers III and V of Alzheimer's disease brains. Neurons immunoreactive for caspase-3 cleaved alphaIIspectrin were located predominantly in layers III and V of the inferior frontal and superior temporal cortices of patients with Alzheimer's disease but not age-matched controls. Pyramidal neurons immunoreactive for caspase-3 cleaved alphaIIspectrin invariably displayed SMI-32 immunoreactivity suggesting that caspase-3 activation is a pathological event that may be responsible for the loss of a subset of pyramidal neurons that comprise corticocortical projections.
Ayala-Grosso
C
C
Unidad de Bioquímica, Facultad de Farmacia, Universidad Central de Venezuela, Nueva Granada, Apartado postal 40109, Caracas, Venezuela.
Tam
J
J
Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, C.P./P.O. Box 1005, Pointe Claire, Dorval, Quebec, Canada H9R 4P8.
Roy
S
S
Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, C.P./P.O. Box 1005, Pointe Claire, Dorval, Quebec, Canada H9R 4P8.
Xanthoudakis
S
S
Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, C.P./P.O. Box 1005, Pointe Claire, Dorval, Quebec, Canada H9R 4P8.
Da Costa
D
D
Unidad de Bioquímica, Facultad de Farmacia, Universidad Central de Venezuela, Nueva Granada, Apartado postal 40109, Caracas, Venezuela.
Nicholson
D W
DW
Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, C.P./P.O. Box 1005, Pointe Claire, Dorval, Quebec, Canada H9R 4P8.
Robertson
G S
GS
Departments of Psychiatry and Pharmacology, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5. Electronic address: ROBERTGS@DAL.CA.
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D016900:Neurofilament Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D013049:Spectrin / Q000378:metabolism*
D016900:Neurofilament Proteins; D013049:Spectrin; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases