Correlates of p53- and Fas (CD95)-mediated apoptosis in Alzheimer's disease.
Apoptosis may be an important mechanism of cell loss in Alzheimer's disease (AD). Experimentally, apoptosis is preceded by nuclear accumulation of p53, and increased expression of Fas (CD95) antigen. In the present study, quantitative Western blot analysis of postmortem frontal and temporal lobe tissue demonstrated significantly higher mean levels of p53 and Fas in AD relative to age-matched controls. Immunohistochemical staining and in situ apoptosis assays demonstrated increased p53 and Fas expression and DNA fragmentation in overlapping populations of cortical neurons, and cortical and white matter glial cells distributed in regions damaged by neurodegeneration. Double-label immunohistochemical staining studies revealed p53 immunoreactivity in: 1) cortical neurons without tau-immunoreactive neurofibrillary tangles; 2) numerous, but not all tau-immunoreactive neuropil neurites and white matter axons; 3) dystrophic fibrils surrounding amyloid-beta-immunoreactive plaques; and 4) glial cells characterized as A2B5+ protoplasmic astrocytes or oligodendrocytes. The prominent distribution of dystrophic p53-immunoreactive processes around amyloid-beta-containing plaques suggests that amyloid deposits are associated with local neuritic degeneration. In addition, the results suggest that many tau-immunoreactive neuritic processes originate from degenerating (p53) as well as regenerating neurons. Finally, apoptosis of glial cells (A2B5+) required to maintain the functional integrity of axons and dendrites may represent an important pathogenic mechanism of axonal loss and synaptic disconnection in AD.
de la Monte
S M
SM
Alzheimer's Disease Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston 02129, USA. delamont@helix.mgh.harvard.edu
Sohn
Y K
YK
Wands
J R
JR
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000032:analysis; D017209:Apoptosis / Q000502:physiology*; D001710:Biotin; D002540:Cerebral Cortex / Q000737:chemistry; D053938:DNA Fragmentation; D003856:Deoxyuracil Nucleotides; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D013194:Staining and Labeling; D016159:Tumor Suppressor Protein p53 / Q000032:analysis* / Q000096:biosynthesis; D019014:fas Receptor / Q000032:analysis* / Q000096:biosynthesis; D016875:tau Proteins / Q000032:analysis
D016229:Amyloid beta-Peptides; D003856:Deoxyuracil Nucleotides; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D016875:tau Proteins; D001710:Biotin