Reduction of synaptojanin 1 accelerates Aβ clearance and attenuates cognitive deterioration in an Alzheimer mouse model.
Recent studies link synaptojanin 1 (synj1), the main phosphoinositol (4,5)-biphosphate phosphatase (PI(4,5)P2-degrading enzyme) in the brain and synapses, to Alzheimer disease. Here we report a novel mechanism by which synj1 reversely regulates cellular clearance of amyloid-β (Aβ). Genetic down-regulation of synj1 reduces both extracellular and intracellular Aβ levels in N2a cells stably expressing the Swedish mutant of amyloid precursor protein (APP). Moreover, synj1 haploinsufficiency in an Alzheimer disease transgenic mouse model expressing the Swedish mutant APP and the presenilin-1 mutant ΔE9 reduces amyloid plaque load, as well as Aβ40 and Aβ42 levels in hippocampus of 9-month-old animals. Reduced expression of synj1 attenuates cognitive deficits in these transgenic mice. However, reduction of synj1 does not affect levels of full-length APP and the C-terminal fragment, suggesting that Aβ generation by β- and γ-secretase cleavage is not affected. Instead, synj1 knockdown increases Aβ uptake and cellular degradation through accelerated delivery to lysosomes. These effects are partially dependent upon elevated PI(4,5)P2 with synj1 down-regulation. In summary, our data suggest a novel mechanism by which reduction of a PI(4,5)P2-degrading enzyme, synj1, improves amyloid-induced neuropathology and behavior deficits through accelerating cellular Aβ clearance.
From the Department of Neurology and the Alzheimer's Disease Research Center and.
Li
L
Zhu
Minghao
M
Zhong
Jiaying
J
Zhao
Hannah
H
Rhee
Ina
I
Caesar
Elysse M
EM
Knight
Laura
L
Volpicelli-Daley
Victor
V
Bustos
William
W
Netzer
Lijuan
L
Liu
Louise
L
Lucast
Michelle E
ME
Ehrlich
Nikolaos K
NK
Robakis
Samuel E
SE
Gandy
Dongming
D
Cai
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D000099182:Phosphoinositide 5-Phosphatases
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D019269:Phosphatidylinositol 4,5-Diphosphate; D010744:Phosphoric Monoester Hydrolases; D053764:Presenilin-1; D000099182:Phosphoinositide 5-Phosphatases; C508853:PSEN1 protein, human; C078592:amyloid beta-protein (1-40); C580804:presenilin 1, mouse
Alzheimer Disease; Amyloid; Clearance; Endosomal/Lysosomal Degradation; Intracellular Trafficking; PIP2; Protein Degradation; Synaptojanin 1; Transgenic Mice