BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr³⁴⁸ phosphorylation

Abstract

For molecular and cellular experiments in neurons and in human brain samples AbstractThe bridging integrator 1 gene (BIN1) is a major genetic risk factor for Alzheimer's disease (AD). In this report, we investigated how BIN1-dependent pathophysiological processes might be associated with Tau. We first generated a cohort of control and transgenic mice either overexpressing human MAPT (TgMAPT) or both human MAPT and BIN1 (TgMAPT;TgBIN1), which we followed-up from 3 to 15 months. In TgMAPT;TgBIN1 mice short-term memory deficits appeared earlier than in TgMAPT mice; however -unlike TgMAPT mice -TgMAPT;TgBIN1 mice did not exhibit any long-term or spatial memory deficits for at least 15 months. After sacrifice of the cohort at 18 months, immunohistochemistry revealed that BIN1 overexpression prevents both Tau mislocalization and somatic inclusion in the hippocampus, where an increase in BIN1-Tau interaction was also observed. We then sought mechanisms controlling the BIN1-Tau interaction. We developed a high-content screening approach to characterize modulators of the BIN1-Tau interaction in an agnostic way (1,126 compounds targeting multiple pathways), and we identified -among others -an inhibitor of Calcineurin, a Ser/Thr phosphatase. We determined that Calcineurin dephosphorylates BIN1 on a Cyclin-dependent kinase phosphorylation site at T348, promoting the open conformation of the neuronal BIN1 isoform.Phosphorylation of this site increases the availability of the BIN1 SH3 domain for Tau interaction, as demonstrated by nuclear magnetic resonance experiments and in primary neurons. Finally, we observed that the levels of the neuronal BIN1 isoform were decreased in AD brains, whereas phospho-BIN1(T348):BIN1 ratio was increased, suggesting a compensatory mechanism. In conclusion, our data support the idea that BIN1 modulates the AD risk through an intricate regulation of its interaction with Tau. Alteration in BIN1 expression or activity may disrupt this regulatory balance with Tau and have direct effects on learning and memory.

Differential transcript usage unravels gene expression alterations in Alzheimer’s disease human brains

“…This observation is in line with decreased BIN1 isoform 1 protein expression in the AD brain compared with controls (our own results; Glennon et al, 2013). This would be also in agreement with the observation that an overexpression of the BIN1 isoform 1 may be protective in a model of Tauopathy (Sartori et al, 2019).…”

The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis?

“…In addition, a functional risk variant of BIN1 has been associated with Tau loads (but not Aβ loads) in AD brains [18]. Furthermore, human BIN1 directly binds Tau and this interaction in neurons depends on the level of BIN1 expression, as well as the phosphorylation statuses of both BIN1 and Tau [85, 89, 110, 124]. Moreover, human BIN1 overexpression in a mouse model of tauopathy has been shown to increase BIN1–Tau interaction in the neuronal network and to rescue long-term memory deficits and Tau somatic inclusions induced by human Tau overexpression [110].…”

A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity

“…Tau's proline-rich domain binds directly to BIN1's SH3 domain and phosphorylation of Tau regulates this binding (47), highlighting a potential role for the Tau-BIN1 interaction in Tau-mediated AD deficits. A recent report used Tau-BIN1 PLA to identify modulators of Tau-BIN1 interaction (48) and found that phosphorylation of BIN1 modulates the interaction and that there is altered BIN1 phosphorylation in AD brain.…”