Involvement of apoptosis and cholinergic dysfunction in Alzheimer's disease

As Alzheimer’s disease (AD) progresses, brain atrophy becomes conspicuous, and histologically there is neuronal loss, primarily with a deficit of cholinergic neurons observed. Hitherto, the view has been that cell death, apoptosis, plays a role in this neuronal loss. Apoptosis is characterized by the morphological changes of nuclear fragmentation, chromatin condensation and cell shrinkage, with activation of caspases, members of the cysteine protease family, resulting in considerable substrate cleavage. TUNEL positive neurons have in fact been detected in AD brain, indicating increased caspase activity and resulting substrate cleavage. In AD brain, amyloid beta peptides (Aβ), the main constituent of senile plaque, are a specific pathological hallmark observed in extracellular spaces. In contrast, the main constituent of intracellularly observed neurofibrillary tangles (NFT) is hyperphosphorylated tau, which is observed in various neurodegenerative disorders other than AD. The viewpoint of many studies is that the Aβ and NFT that cause these neuropathological changes probably participate in neuronal death. However, up until now it has been thought that there was no hypothesis offering a comprehensive explanation of how the accumulation of extracellular Aβ and intracellular NFT leads to neuronal death. This report first covers the mechanism of apoptosis as clarified by molecular biological methods, and provides an explanation of how apoptosis could be involved in AD pathology. The subject of autophagic cell death, a type of cell death morphology that has recently been the focus of attention, is also addressed.