水I . Introduction of ADII. How does presenilin(PS) mutationsperturb ER Ca2+ release?III. How does β-Amyloid(Aβ) disturbintracellular Ca2+ homeostasis?
Content Ⅰ. Introduction of AD Ⅱ. How does presenilin(PS) mutations perturb ER Ca2+ release？ Ⅲ. How does β-Amyloid(Aβ) disturb intracellular Ca2+ homeostasis？
ADpathologicalhallmarks:deposition of amyloidplaques and neurofibrillarytangles,neuronalloss,synapticdegeneration.pathogenesis:amyloid hypothesishyperphosphorylated tau hypothesis, calciumhomeostasishypothesisPS: an integral membrane protein in the ER of neurons1. increased production of Aβ1-42 which thenaggregates and damages neurons.2. intense sparks of Ca2+ emanating from withinneuronsAβ:self-aggregated into amyloidfibrilsAPP蛋白：β切割细胞膜切割=presenilins（40/42）N端C端
Ⅰ. Introduction • AD pathological hallmarks: deposition of amyloid plaques and neurofibrillary tangles, neuronal loss, synaptic degeneration. pathogenesis: amyloid hypothesis, hyperphosphorylated tau hypothesis, calcium homeostasis hypothesis • PS: an integral membrane protein in the ER of neurons 1. increased production of Αβ1-42 which then aggregates and damages neurons. 2. intense sparks of Ca2+ emanating from within neurons • Aβ: self-aggregated into amyloid fibrils
福enhancedchannelabundanceofER(levelsofnyanodine receptors are elevated in primaryhippocampal neurons from PS1 mutant knockinmice)Chan SL,et al.2000enhancedchannelactivityofERinresponsetoits ligand(lnsP3 activated Ca2+ release is useddiagnostically to identify individuals with FAD)Cheung KH, et al.2010
Ⅱ. How does PS mutations perturb ER Ca2+ release？ • enhanced channel abundance of ER(levels of ryanodine receptors are elevated in primary hippocampal neurons from PS1 mutant knockin mice) Chan SL, et al. 2000 • enhanced channel activity of ER in response to its ligand(InsP3 activated Ca2+ release is used diagnostically to identify individuals with FAD) Cheung KH, et al. 2010
Hippocampus100BasolinePoak80()780)Cerebellum6040201.61.20PS1M146VKI0.80.4PS1M146VPS1M146V43HippocampusCerebellumLevelsofRyRmRNAareincreasedPS1andRyRproteinsinprimaryneuronsexpressingarecolocalizedmutantPS1ChanSL,etal.2000
Presenilin-1 Mutations Increase Levels of Ryanodine Receptors and Calcium Release Levels of RyR mRNA are increased in primary neurons expressing mutant PS1 PS1 and RyR proteins are colocalized Chan SL, et al. 2000
-1.00.80.60.4P0.2P0.099080EIIMISdIMZSd108101080Pd99IMISdA18MOS1082819028VCheungKH,etal.2010
Multiple FAD PS mutations modulate InsP3R channel gating by mode switching Cheung KH, et al. 2010