Excess synaptojanin 1 drives age-dependent cognitive deficits, a unifying mechanism for individuals at high risk of Alzheimer's disease
Andre M. Miranda1,2,7, Mathieu Herman1,7, Rong Cheng1,7, Eden Nahmani1, Geoffrey Barrett1, Elizabeta Micevska1, Gaelle Fontaine3, Marie-Claude Potier3, Elizabeth Head4, Frederick A. Schmitt4, Ira T. Lott4,5, Stylianos E. Antonarakis6, Gilbert Di Paolo1, Joseph H. Lee1, S. Abid Hussaini1, Catherine Marquer1
1Columbia University Medical Center, New York City, USA; 2University of Minho, Braga, Portugal; 3ICM, Paris, France; 4University of Kentucky, Lexington, USA; 5University of California-Irvine, Orange, USA; 6University of Geneva Medical School, Geneva, Switzerland
The three forms of Alzheimer's disease -familial (FAD), Down syndrome-related (DS/AD) and sporadic (SAD)- share common clinical and neuropathology signatures. While early-onset FAD is caused by mutations in the APP, PSEN1 or PSEN2 genes and DS/AD is due to triplication of human chromosome 21 (Hsa21), the most potent genetic risk factor for SAD is APOE4. A recent study reported that APOE4 carriers show increased levels of synaptojanin 1 (SYNJ1), a critical regulator of synaptic vesicle trafficking. SYNJ1 is coded by SYNJ1, mapping to Hsa21, and is increased in individuals with DS/AD. Synj1 has been linked to amyloid toxicity and endolysosomal dysfunction, both key features of AD.
Essentially nothing is known on a potential role for SYNJ1 in human FAD. We thus targeted SYNJ1 as a candidate gene that may contribute to phenotypic variations in FAD and found that variants in SYNJ1 were associated with age of onset in both early- and late-onset human FAD cohorts. Taking one step further, we then asked whether the elevated levels of SYNJ1 observed in populations with high risk for AD, directly impact cognition in an age-dependent manner. We show that increased SYNJ1 levels in autopsy brains from adults with DS/AD were inversely correlated with synaptophysin levels, a direct read-out of synaptic integrity. We further report age-dependent cognitive decline in a mouse model over-expressing murine Synj1 to the levels observed in human SAD, triggered through hippocampal hyperexcitability and defects in the spatial reproducibility of place fields.
This work therefore highlights a novel role for SYNJ1 in the function of place cells in the aging hippocampus with critical implications for memory deficits in all three forms of AD and their possible treatment.