The phosphoinositide phosphatase synaptojanin 1 (SYNJ1) is a key regulator of synaptic function. We first tested whether SYNJ1 contributes to phenotypic variations in familial Alzheimer's disease (FAD) and show that SYNJ1 polymorphisms are associated with age of onset in both early- and late-onset human FAD cohorts. We then interrogated whether SYNJ1 levels could directly affect memory. We show that increased SYNJ1 levels in autopsy brains from adults with Down syndrome (DS/AD) are inversely correlated with synaptophysin levels, a direct readout of synaptic integrity. We further report age-dependent cognitive decline in a mouse model overexpressing murine Synj1 to the levels observed in human sporadic AD, triggered through hippocampal hyperexcitability and defects in the spatial reproducibility of place fields. Taken together, our findings suggest that SYNJ1 contributes to memory deficits in the aging hippocampus in all forms of AD. Miranda et al. combine human genetics, human brain samples, and behavior and electrophysiology in a transgenic mouse model to show that synaptojanin 1 levels regulate the function of place cells in the aging hippocampus. The results have implications for memory deficits in all types of Alzheimer's disease.
|Number of pages||9|
|State||Published - Jun 5 2018|
Bibliographical noteFunding Information:
We would like to thank Agnieszka Staniszewski and Dr. Ottavio Arancio for their expert help with behavior studies. We would like to thank Eric Doran and Dr. Sarah B. Martin for their help with DS studies. We want to acknowledge Valerie Savage, Alejandro J. Mercado-Capote, Adithi Jayaraman, and Masayuki Yanagiba for help with microdrive construction and spike sorting. We also want to thank Nicoletta Barolini for her expert help with illustrations and graphics. This work was supported by grants from Fundação para a Ciência e Tecnologia ( PD/BD/105915/2014 to A.M.M.), the Philippe Chatrier Foundation (C.M.), the Lejeune Foundation ( 1149 to G.D.P.), the Alzheimer’s Association ( 2015-NIRG-341570 to S.A.H.), ANR Investissements d’Avenir ( ANR-10-IAIHU-06 to M.-C.P.), and the NIH ( R01AG050425 to S.A.H.; RO1HD064993 to E.H. and F.A.S.; and RO1HD065160, P50AG16573, and U01AG051412 to I.T.L.). Data collection on Caribbean Hispanic families with at least one G206A founder mutation in the PSEN1 gene was supported by the BrightFocus Foundation ( A2015633S ) and NIH /National Institute on Aging ( NIA ) ( R56 AG051876-01A1 ) to J.H.L. Data collection for the EFIGA project was supported by the Genetic Studies of Alzheimer’s Disease in Caribbean Hispanics (EFIGA), funded by the NIH/NIA ( 5R37AG015473 , RF1AG015473 , and R56AG051876 ). We acknowledge the EFIGA study participants and the EFIGA research and support staff for their contributions to this study.
© 2018 The Authors
- Long-term memory
- in vivo electrophysiology
- neurodegenerative disorders
- single nucleotide polymorphisms
- synaptic dysfunction
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)