Abstract
Neurodegenerative disorders are morphologically featured by progressive cell loss in specific vulnerable neuronal populations of the brain and/or spinal cord, often associated with typical cytoskeletal protein changes forming intracytoplasmic and/or intra-nuclear inclusions and gliosis. In Alzheimer’s disease (AD), the most common type of dementia in advanced age, loss of cortical neurons and synapses is accompanied by extracellular deposition of Aβ4 amyloid peptide (Aβ) in senile plaques and cerebral vessels. Paired helical filaments containing hyperphosphorylated microtubule-associated tau protein forming neurofibrillary tangles (NFT), neuropil threads, and neuritic plaques are other histopathological hallmarks of AD (1). In Parkinson’s disease (PD), the most frequent extrapyramidal movement disorder in adults, neuron loss in substantia nigra (SN) and other subcortical nuclei is associated with widespread occurrence of intracytoplasmic Lewy bodies (LB) formed from fibrillary α-synuclein and hyperphosphorylated neurofilament protein (2–5). Frequent cortical LBs occur in dementia with Lewy bodies (DLB), which is the second most frequent type in adult age dementia (6), but small numbers are also seen in both PD and AD (7,8). In Pick disease (PiD), a rare presenile type of frontotemporal dementia (FTD), progressive cortical degeneration is associated with Pick bodies, intracytoplasmic accumulations of hyperphosphorylated tau protein (9–11). In multisystem atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), which are rigid-akinetic extrapyramidal disorders, multisystemic neuronal degeneration is accompanied by glial cytoplasmic inclusions (GCI) containing tau protein that differs from that in AD and PiD (2,10,11) and a-synuclein (12). In Huntington disease (HD), an autosomal dominantly inherited hyperkinetic extrapyramidal disorder resulting from mutation of the IT-15 gene on chromosome 4p16.3 with expanded polyglutamine CAG repeats, neurodegeneration in man and transgenic mice is related to neuronal intranuclear inclusions containing huntingtin and ubiquitin (13,14). Similar inclusions are seen in other rare autosomal dominant ataxic polyglutamine disorders (e.g., dentatorubropallidoluysian atrophy [DRPLA]), suggesting that these protein aggregates are a common feature of the pathogenesis of glutamine repeat neurodegenerations (13,15). In amyotrophic lateral sclerosis (ALS), which is an adult neurodegenerative disease of both lower and upper motor neurons, skein-like ubiquitin-containing inclusions are seen (16). The nature, time-course, and molecular causes of cell death and their relation to abnormal cytoskeletal protein aggregations, in these and other neurodegenerative disorders, are a matter of considerable controversy. Recent studies have provided new insights into cell death programs and their roles in neurodegeneration that will be discussed in this chapter.
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Jellinger, K.A. (2003). Apoptosis vs Nonapoptotic Mechanisms in Neurodegeneration. In: Wood, P.L. (eds) Neuroinflammation. Contemporary Neuroscience. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-297-5_2
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