P53-ASSOCIATED AND CD95-ASSOCIATED APOPTOSIS IN NEURODEGENERATIVE DISEASES

Apoptosis is likely to be an important mechanism of cell loss in neuro degenerative diseases, but the signaling cascades activated before DNA fragmentation have nut yet been determined. p53 or CD95 gene up-regul ation precedes apoptosis in many cell types, and a potential role for these molecules in apoptosis of neurons and glial cells has already be en demonstrated in Alzheimer's disease (AD). To determine whether apop tosis in other neurodegenerative diseases is mediated by similar mecha nisms, p53 and CD95 expression were examined in postmortem central ner vous system tissues from patients with diffuse Lewy body disease (DLBD ), Pick's disease (PkD), progressive supranuclear palsy (PSP), multipl e system atrophy (MSA), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Down's syndrome plus Alzheimer's disease (DN+AD). Quantitative immunoblot analysis demonstrated higher temporal lobe le vels of p53 and CD95 proteins in DLBD, PkD, and DN+AD, and higher temp oral lobe levels of CD95 only in MSA and PSP relative to PD and aged c ontrols (for all, p < 0.01). In histologic sections, increased p53 imm unoreactivity was localized in neuronal and glial cell nuclei, neurona l perikarya, and dystrophic neuritic and glial cell processes in the f rontal (Area 11) and temporal (Area 21) robes in DLBD, PkD, and DN+AD, the motor cortex and spinal ventral horns in ALS, and the striatum an d midbrain in DLBD, MSA, PD, and PSP. Increased CD95 expression and nu clear DNA fragmentation were present in the same cell types and struct ures that manifested increased nuclear p53 immunoreactivity. The resul ts suggest that p53- or CD95-associated apoptosis may be a common mech anism of cell loss in several important neurodegenerative diseases. In addition, the presence of abundant p53-immunoreactive neurites and gl ial cell processes appears to be a novel feature of neurodegeneration shared by these distinct diseases.