Problems of cell death in neurodegeneration and Alzheimer's Disease

Progressive cell loss in specific neuronal populations is a pathological hallmark of neurodegenerative diseases, but its mechanisms remain unresolved. Apoptosis or alternative pathways of neuronal death have been discussed in Alzheimer disease (AD) and other disorders. However, DNA fragmentation in human brain as a sign of neuronal injury is too frequent to account for the continuous loss in these slowly progressive diseases. In autopsy cases of AD, Parkinson's disease (PD), related disorders, and age-matched controls, DNA fragmentation using the TUNEL method and an array of apoptosis-related proteins (ARP), proto-oncogenes, and activated caspase 3, the key enzyme of late-stage apoptosis, were examined. In AD, a considerable number of hippocampal neurons and glial cells showed DNA fragmentation with a 3- to 6-fold increase related to amyloid deposits and neurofibrillary tangles, but only one in 2.600 to 5.650 neurons displayed apoptotic morphology and cytoplasmic immunoreactivity for activated caspase 3, whereas no neurons were labeled in age-matched controls. Caspase 3 immunoreactivity was seen in granules of cells with granulovacuolar degeneration, in around 25% co-localized with early cytoplasmic deposition of tau-protein. In progressive supranuclear palsy, only single neurons but oligodendrocytes in brainstem, around 25% with tau-inclusions, were TUNEL-positive and expressed both ARPs and activated caspase 3. In PD, dementia with Lewy bodies, and multisystem atrophy (MSA), TUNEL-positivity and expression of ARPs or activated caspase 3 were only seen in microglia and oligodendrocytes with cytoplasmic inclusions in MSA, but not in neurons. These data provide evidence for extremely rare apoptotic neuronal death in AD and PSP compatible with the progression of neuronal degeneration in these chronic diseases. Apoptosis mainly involves reactive microglia and oligodendroglia, the latter occasionally involved by deposits of insoluble fibrillary proteins, while alternative mechanisms of neuronal death may occur. Susceptible cell populations in a proapoptotic environment, particularly in AD, show increased vulnerability towards metabolic or other noxious factors, with autophagy as a possible protective mechanism in early stages of programmed cell death. The intracellular cascade leading to cell death still awaits elucidation.