Alzheimer disease(AD) is the most common neurodegenerative disorder worldwide and is at present,incurable.The accumulation of toxic amyloid-beta(Aβ) peptide aggregates in AD brain is thought to trigger the extensive ...Alzheimer disease(AD) is the most common neurodegenerative disorder worldwide and is at present,incurable.The accumulation of toxic amyloid-beta(Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline,an idea that underlies the'amyloid hypothesis'of AD etiology in both the familal(FAD) and sporadic forms of the disease.Genetic mutations causing FAD also result in the dysregulation of neuronal calcium(Ca2+) handling and may contribute to AD pathogenesis,an idea termed the'calcium hypothesis'of AD.Mutations in presenilin proteins account for majority of FAD cases.Presenilins function as catalytic subunit ofγ-secretase involved in generation of Aβ peptide Recently,we discovered that presenilns function as low-conductance,passive ER Ca2+ leak channels,independent of γ-secretase activity.We further discovered that many FAD mutations in presenilins result in loss of ER Ca2+ leak function activity and Ca2+ overload in the ER.These results provided potential explanation for abnormal Ca2+ signaling observed in FAD cells with mutations in presenilns.Our latest work on studies of ER Ca2+ leak channel function of presenilins and implications of these findings for understanding AD pathogenesis are discussed in this article.展开更多
基金supported by the McKnight Neuroscience of Brain Disorders Award and NIH grant R01AG030746
文摘Alzheimer disease(AD) is the most common neurodegenerative disorder worldwide and is at present,incurable.The accumulation of toxic amyloid-beta(Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline,an idea that underlies the'amyloid hypothesis'of AD etiology in both the familal(FAD) and sporadic forms of the disease.Genetic mutations causing FAD also result in the dysregulation of neuronal calcium(Ca2+) handling and may contribute to AD pathogenesis,an idea termed the'calcium hypothesis'of AD.Mutations in presenilin proteins account for majority of FAD cases.Presenilins function as catalytic subunit ofγ-secretase involved in generation of Aβ peptide Recently,we discovered that presenilns function as low-conductance,passive ER Ca2+ leak channels,independent of γ-secretase activity.We further discovered that many FAD mutations in presenilins result in loss of ER Ca2+ leak function activity and Ca2+ overload in the ER.These results provided potential explanation for abnormal Ca2+ signaling observed in FAD cells with mutations in presenilns.Our latest work on studies of ER Ca2+ leak channel function of presenilins and implications of these findings for understanding AD pathogenesis are discussed in this article.
