Variants in the gene for the lipid phosphatase synaptojanin 1 alter the age of onset in familial Alzheimer’s disease, says a new study. The work, from Catherine Marquer’s lab at Columbia University Medical Center in New York, also links overexpression of the gene to synapse loss in adults with Down’s syndrome/AD. In mice, elevation of synaptojanin 1 expression hypes up hippocampal neurons, to the detriment of memory. The study, which appeared June 5 in Cell Reports, raises the prospect that this brain-specific enzyme could offer a potential therapeutic target for memory impairment.
- Synaptojanin 1 variants reported to affect age of onset in FAD.
- High levels of this lipid phosphatase come with low synaptophysin in adults with Down’s syndrome.
- Overexpression in mice causes hippocampal excitability, memory problems.
In neurons, synaptojanin 1 catalyzes the dephosphorylation of membrane phosphoinositides. This is important for regulating synaptic vesicle recycling after neurotransmitter release. Its expression is elevated in two groups of people at risk for AD—carriers of the ApoE4 allele (Zhu et al., 2015), and people with Down’s syndrome (Martin et al., 2014). In animal models of AD, reducing synaptojanin 1 levels improves pathological measures and behavior (Zhu et al., 2013; McIntire et al., 2012; Apr 2008 news).
In the new work, first authors Andre Miranda, Mathieu Herman, and Rong Cheng offer genetic evidence to implicate synaptojanin 1 in additional, familial forms of AD. They identified variants associated with age of onset or memory function in a family with early Alzheimer disease due to the PSEN1 G206A mutation. In a different cohort of late-onset familial AD, they associate two SYNJ1 haplotypes with age of onset. The variants are in regions likely to influence gene function or expression, the scientists claim.
Examination of postmortem brain tissue from adults with Down’s syndrome revealed a potential link between synaptojanin 1 expression and synapse loss. The investigators found a modest inverse correlation between synaptojanin 1 levels and synaptophysin, a marker of synapse number—when synaptojanin 1 was high, synaptophysin, and presumably synapse number, dropped. The authors did not see the correlation in younger people with Down’s syndrome, in whom synaptojanin 1 levels were not yet elevated.
To directly test what excess synaptojanin 1 does to synaptic function, the scientists turned to a transgenic mouse overexpressing murine synj1. With a 76 percent surfeit of synaptojanin 1 protein compared to wild-type, the mice recapitulate the overexpression reported for ApoE4 carriers with early onset AD. The mice displayed no changes in synaptophysin or the postsynaptic marker PSD95, suggesting their synapses were intact. However, synaptic function was not. In two hippocampal-dependent memory tasks, the mice displayed age-related defects. In the radial arm water maze, young transgenic mice learned and remembered how to find a platform as well as the wild-type. However, as they got older, the transgenic mice seemed to forget the platform location from day to day when repeatedly tested. A fear conditioning test yielded similar results, where the transgenic mice seemed to forget the contextual cues they’d learned in the session before.
This may have been due to dysfunction of place cells in the hippocampus: When the investigators implanted electrodes in the hippocampi of mice and recorded neuronal firing in freely moving animals, the place cells in transgenics responded to locations less accurately and with more variability than those in wild-type animals. “Normally, we would see good repetition of firing at a specific location, but in the transgenic, the neurons fired at the correct location one day, but the next day they were not able to fire at the same location in the exact same way,” Marquer said. This could explain why the mice seemed a bit lost on their second day in the water maze, she said.
If increased synaptojanin 1 worsens memory, then inhibiting the enzyme could become a therapeutic strategy, the authors suggest. The right balance may be hard to strike, however, since loss-of-function mutations in synaptojanin 1 cause early onset Parkinson’s disease, seizures, and tau pathology (Dyment et al., 2015). “We want to inhibit the excess activity, but don’t want to go further than threshold level of normal function. We would need more of a regulator than complete inhibitor,” said Marquer.
William Mobley, University of California, San Diego, said the data support the role of synaptojanin 1 in synapse decline, but took a cautious view of its salience as a drug target. “It is one of several different genes that regulate endocytosis and should be looked at in the future in preclinical models. But one should not jump to the conclusion that this is the only, or the most important, cause of endosome dysfunction in AD,” he told Alzforum. The amyloid precursor protein, and its products, also regulate endosomes, and their role must be taken into account, Mobley said.—Pat McCaffrey
- Zhu L, Zhong M, Elder GA, Sano M, Holtzman DM, Gandy S, Cardozo C, Haroutunian V, Robakis NK, Cai D. Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):11965-70. Epub 2015 Sep 8 PubMed.
- Martin SB, Dowling AL, Lianekhammy J, Lott IT, Doran E, Murphy MP, Beckett TL, Schmitt FA, Head E. Synaptophysin and synaptojanin-1 in Down syndrome are differentially affected by Alzheimer's disease. J Alzheimers Dis. 2014;42(3):767-75. PubMed.
- Zhu L, Zhong M, Zhao J, Rhee H, Caesar I, Knight EM, Volpicelli-Daley L, Bustos V, Netzer W, Liu L, Lucast L, Ehrlich ME, Robakis NK, Gandy SE, Cai D. Reduction of synaptojanin 1 accelerates Aβ clearance and attenuates cognitive deterioration in an Alzheimer mouse model. J Biol Chem. 2013 Nov 1;288(44):32050-63. PubMed.
- McIntire LB, Berman DE, Myaeng J, Staniszewski A, Arancio O, Di Paolo G, Kim TW. Reduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer's disease. J Neurosci. 2012 Oct 31;32(44):15271-6. PubMed.
- Dyment DA, Smith AC, Humphreys P, Schwartzentruber J, Beaulieu CL, FORGE Canada Consortium, Bulman DE, Majewski J, Woulfe J, Michaud J, Boycott KM. Homozygous nonsense mutation in SYNJ1 associated with intractable epilepsy and tau pathology. Neurobiol Aging. 2015 Feb;36(2):1222.e1-5. Epub 2014 Sep 6 PubMed.
No Available Further Reading
- Miranda AM, Herman M, Cheng R, Nahmani E, Barrett G, Micevska E, Fontaine G, Potier MC, Head E, Schmitt FA, Lott IT, Jiménez-Velázquez IZ, Antonarakis SE, Di Paolo G, Lee JH, Hussaini SA, Marquer C. Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease. Cell Rep. 2018 Jun 5;23(10):2967-2975. PubMed.