BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 implicated in Tau pathology

Taga, M.; Petyuk, V. A.; White, C.; Marsh, G.; Ma, Y.; Klein, H.-U.; Connor, S. M.; Khairallah, A.; Olah, M.; Schneider, J.; Ransohoff, R.; Bennett, D. A.; Crotti, A.; Bradshaw, E. M.; De Jager, P. L.

doi:10.1101/535682

bioRxiv · 10.1101/535682

BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 implicated in Tau pathology

Taga, M.·Petyuk, V. A.·White, C.·Marsh, G.·Ma, Y.·Klein, H.-U.·Connor, S. M.·Khairallah, A.·Olah, M.·Schneider, J.·Ransohoff, R.·Bennett, D. A.·Crotti, A.·Bradshaw, E. M.·De Jager, P. L.

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Abstract

Identified as an Alzheimers disease (AD) susceptibility gene by genome wide-association studies, BIN1 has 10 isoforms that are expressed in the Central Nervous System (CNS). The distribution of these isoforms in different cell types, as well as their role in AD pathology still remains unclear. Utilizing antibodies targeting specific BIN1 epitopes in human postmortem tissue and analyzing RNA expression data from purified microglia, we identified three isoforms expressed specifically in neurons (isoforms 1, 2 and 3) and four isoforms expressed in microglia (isoforms 6, 9, 10 and 12). The abundance of selected peptides, which correspond to groups of BIN1 protein isoforms, was measured in dorsolateral prefrontal cortex, and their relation to neuropathological features of AD was assessed. Peptides contained in exon 7 of BIN1s N-BAR domain were found to be significantly associated with AD-related traits and, particularly, tau pathology. Since only isoforms 1, 2 and 3 contain exon 7, it appears that decreased protein expression of the N-BAR domain of BIN1 is associated with greater accumulation of tau pathology and subsequent cognitive decline, with astrocytic rather than neuronal BIN1 being the more likely culprit. These effects are independent of the BIN1 AD risk variant, suggesting that targeting specific BIN1 isoforms might be a novel therapeutic approach to prevent the accumulation of tau pathology.

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Taga, M., Petyuk, V. A., White, C., Marsh, G., Ma, Y., Klein, H.-U., Connor, S. M., Khairallah, A., Olah, M., Schneider, J., Ransohoff, R., Bennett, D. A., Crotti, A., Bradshaw, E. M., De Jager, P. L.. 2019-01-30. BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 implicated in Tau pathology. https://doi.org/10.1101/535682

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