Our lab has been investigating how the second most common late-onset Alzheimer's disease risk genes, namely BIN1, contributes to neuropathology. BIN1 is an adaptor protein that regulates membrane dynamics in a variety of cellular contexts. BIN1 (also referred to as amphiphysin II) is a member of the BAR (Bin/Amphiphysin/ Rvs) adaptor family proteins that regulate membrane dynamics in the context of endocytosis and membrane remodeling. The BIN1 gene undergoes complex alternative splicing to generate more than 15 tissue-specific and ubiquitous and isoforms, which differ in their tissue distribution, subcellular localization, and function. Only limited information is available on BIN1 expression and function in the brain. As such, there is much to be learned about the precise biological and mechanistic connection between BIN1 and Alzheimer's disease.
We characterized BIN1 expression in human and rodent brains by immunohistochemistry and immunoblotting using a panel of BIN1 antibodies. Contrary to what has been reported in previous studies, we observed striking BIN1 localization to white matter tracts in rodent and the human brain. Detailed characterization revealed that the large majority of BIN1 in the human brain is expressed in mature oligodendrocytes whereas neuronal BIN1 represents a minor fraction. In an agreement, the loss of BIN1 immunoreactivity significantly correlates with the extent of demyelination in multiple sclerosis lesions. These findings are consistent with the upregulation of BIN1 expression at the onset of postnatal myelination in the rodent brain and during differentiation of cultured oligodendrocytes. The predominant non-neuronal BIN1 localization contrasts with the strict neuronal expression and presynaptic localization of the BIN1 paralog, Amphiphysin 1.
How BIN1 might function as a risk factor in AD is far from clear. Although BIN1 has been shown to bind to Tau in vitro, our results indicate that BIN1 immunoreactivity in human AD is not associated with neurofibrillary tangles. Moreover, BIN1 is not expressed by resting and activated microglia, astrocytes, or macrophages in human AD. Our ongoing efforts are aimed at characterizing the BIN1 isoform diversity in the human brain during AD pathogenesis, and to develop novel insights into BIN1 function in the nervous system through the characterization of BIN1 cKO and transgenic mice.
De Rossi P, Buggia-Prévot V, Andrew RJ, Krause SV, Woo E, Nelson PT, Pytel P, and Thinakaran G: BIN1 localization is distinct from Tau tangles in Alzheimer’s disease. Matters, 2017. Full Text
De Rossi P, Buggia-Prévot V, Clayton BLL, Vasquez JB, van Sanford C, Andrew RJ, Lesnick R, Botté A, Deyts C, Salem S, Rao E, Rice RC, Parent A, Kar S, Popko B, Pytel P, Estus S, and Thinakaran G: Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts. Mol. Neurodegener. 2016, 11:59. DOI 10.1186/s13024-016-0124-1. Full Text