Reduction of synaptojanin 1 accelerates Aβ clearance and attenuates cognitive deterioration in an Alzheimer mouse model.

Abstract

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.

• Authors: Li Zhu, Minghao Zhong, Jiaying Zhao, Hannah Rhee, Ina Caesar, Elysse M Knight, Laura Volpicelli-Daley, Victor Bustos, William Netzer, Lijuan Liu, Louise Lucast, Michelle E Ehrlich, Nikolaos K Robakis, Samuel E Gandy, Dongming Cai
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 44 Pg. 32050-63 (Nov 01 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 24052255 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Amyloid beta-Peptides
• PSEN1 protein, human
• Peptide Fragments
• Phosphatidylinositol 4,5-Diphosphate
• Presenilin-1
• amyloid beta-protein (1-40)
• presenilin 1, mouse
• Phosphoric Monoester Hydrolases
• phosphoinositide 5-phosphatase
• Amyloid Precursor Protein Secretases

Topics

• Alzheimer Disease (genetics, metabolism, pathology)
• Amyloid Precursor Protein Secretases (genetics, metabolism)
• Amyloid beta-Peptides (genetics, metabolism)
• Animals
• Cell Line, Tumor
• Disease Models, Animal
• Down-Regulation (genetics)
• Gene Knockdown Techniques
• Hippocampus (metabolism, pathology)
• Humans
• Lysosomes (genetics, metabolism)
• Mice
• Mice, Transgenic
• Mutation
• Peptide Fragments (genetics, metabolism)
• Phosphatidylinositol 4,5-Diphosphate (genetics, metabolism)
• Phosphoric Monoester Hydrolases (biosynthesis, genetics)
• Presenilin-1 (genetics, metabolism)