TY - CHAP M1 - Book, Section TI - Neurodegeneration A1 - Nestler, Eric J. A1 - Hyman, Steven E. A1 - Holtzman, David M. A1 - Malenka, Robert C. PY - 2015 T2 - Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3e AB - Neurodegenerative diseases, of which Alzheimer disease and Parkinson disease are the most common, are a large and diverse group of neurologic disorders characterized by death of neurons.The major processes by which neurons die are necrosis and apoptosis (programmed cell death); both processes involve cascades of proteins including proteolytic enzymes of the caspase family. These mechanisms, once thought entirely distinct, have significant overlap.Processes that can initiate cell death include mitochondrial dysfunction, excitotoxicity, oxidative stress, and abnormal protein aggregation.Abnormal mitochondrial function plays a key role in apoptosis and other forms of neurodegeneration.Excitotoxicity involves excessive activation of neurons via stimulation of glutamate receptors or other mechanisms of depolarization, which trigger biochemical cascades—many of them secondary to excessive Ca2+ flux into neurons—that lead to cell death.The pathologic hallmarks of Alzheimer disease, the most common cause of severe memory impairment in the elderly, are senile plaques, neurofibrillary tangles, dystrophic neurites, and neuronal loss.The development of Alzheimer disease may be due to the improper biochemical processing of amyloid precursor protein (APP) and the subsequent accumulation of β amyloid. A role for the microtubule-associated protein tau has also been implicated.Inherited forms of Alzheimer disease have been linked to mutations in APP or in proteins called presenilins, which regulate the processing of APP and several other proteins.Currently there is no effective treatment for Alzheimer disease, although several pharmacologic strategies for preventing the buildup of β amyloid, promoting its clearance, or counteracting its deleterious effects appear promising.Frontotemporal dementias comprise several other neurodegenerative disorders, roughly half of which involve abnormal aggregation of tau.Loss of dopamine input to the basal ganglia causes the symptoms of Parkinson disease; restoration of dopamine function, for example, with the dopamine precursor L-dopa, remains the mainstay of therapy for the disease.Rare familial forms of Parkinson disease are caused by mutation in several genes related to protein aggregation, including α-synuclein and parkin.Huntington disease is caused by a mutation in the gene for huntingtin; the mutation increases the number of glutamine residues expressed in the protein, which is pathogenic.Amyotrophic lateral sclerosis (ALS) is caused by the selective death of upper motor neurons in the cerebral cortex and/or lower motor neurons in the spinal cord. SN - PB - McGraw-Hill Education CY - New York, NY Y2 - 2024/03/28 UR - neurology.mhmedical.com/content.aspx?aid=1105917072 ER -