. Loss of Bin1 Promotes the Propagation of Tau Pathology. Cell Rep. 2016 Oct 18;17(4):931-940. PubMed.

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  1. It is well accepted that knowledge of the genetic determinants of AD should improve our understanding of the fundamental disease processes. However, when identified, it is often difficult to understand how genetic variants mechanistically contribute to AD pathogenesis. Two methodological possibilities can be developed to pave the way for such understanding: systematic approaches based on medium/high throughput technologies, and hypothesis-driven strategies.

    Calafate et al. chose the latter to determine how BIN1, the second strongest genetic risk factor for AD after APOE, may be involved in the AD processes. Based on the well-characterized function of BIN1 in endocytosis, they proposed, in this elegant paper that describes the use of microfluidic devices, that BIN1 may control tau aggregate entry into the cell though clathrin-dependent endocytic influx. This would lead to propagation of tau pathology from neuron to neuron after aggregates of tau permeabilize the endosome membrane. In this model, underexpression of the neuronal BIN1 isoforms would be deleterious by favoring the internalization of tau aggregates. This hypothesis is in line with the observation that expression of BIN1 may mediate AD genetic risk by modulating tau pathology (Chapuis et al, 2013; Dourlen et al., 2016). Furthermore, it also has been reported that the number of BIN1-positive pyramidal neurons in the CA1 of the hippocampus correlated with hippocampal neuritic plaque scores in AD patients as judged by CERAD criteria (Adams et al., 2016). However, it is important to note that this tau propagation is just one way BIN1 genetic variants might influence AD pathogeneis. There are others:

    (i) BIN1 has been shown to directly interact with tau in a phosphorylation-dependent manner in rat neurons (Sottejeau et al., 2016). From this observation, and additional results, we postulated that the BIN1-tau complex could be at the interface between the actin and microtubule network and that its deregulation may impact neuronal function (Sottejeau et al., 2016).

    (ii) BIN1 has been observed to be mainly expressed in oligodendrocytes (Adams, et al., 2016; De Rossi et al., 2016). This led De Rossi et al. to propose that BIN1 may deregulate myelination.

    (iii) BIN1 has been reported to increase cellular BACE1 levels through impaired endosomal trafficking and reduced BACE1 lysosomal degradation, resulting in increased Aβ production (Myagawa et al., 2016).

    Importantly, depending on the hypothesis, BIN1 overexpression may be deleterious (as proposed by Chapuis et al.) or protective (as suggested by Calafate et al.). However, there is still no consensus about the potential over- or underexpression of BIN1 in the brain even if genetic variants associated with increased AD risk have been linked to a potential overexpression of this gene in vivo and in vitro (Chapuis et al., 2013).

    In conclusion, the physiological and pathophysiological roles of BIN1 have to be better dissected since there is still little known about BIN1 in the brain. BIN1 has been mainly studied in the context of its functions in the muscle and related muscular pathology, i.e., myotonic dystrophy (Fugier et al., 2011). Even though the tau propagation hypothesis is interesting, it is important to keep in mind that several GWAS have been published on tauopathies such as Parkinson’s disease, progressive supranuclear palsy, and frontotemporal dementia. Until now, none of them reported variants at the BIN1 locus that reached genome-wide significance. This could imply that BIN1 might be involved in an AD-specific tau pathology, for example linking amyloid and tau. That is why it would be of interest to assess whether the general mechanism described by Calafate et al., is specific to AD (but potentially exacerbated by Aβ peptide), or can take place in other tauopathies or even in other proteinopathies involving neuron-to-neuron propagation.

    References:

    . Subcellular Changes in Bridging Integrator 1 Protein Expression in the Cerebral Cortex During the Progression of Alzheimer Disease Pathology. J Neuropathol Exp Neurol. 2016 Aug;75(8):779-790. Epub 2016 Jun 26 PubMed.

    . Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry. 2013 Feb 12; PubMed.

    . Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts. Mol Neurodegener. 2016 Aug 3;11(1):59. PubMed.

    . Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology. Mol Psychiatry. 2016 Apr 26; PubMed.

    . Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. Nat Med. 2011 Jun;17(6):720-5. Epub 2011 May 29 PubMed.

    . BIN1 regulates BACE1 intracellular trafficking and amyloid-β production. Hum Mol Genet. 2016 May 14; PubMed.

    . Tau phosphorylation regulates the interaction between BIN1's SH3 domain and Tau's proline-rich domain. Acta Neuropathol Commun. 2015 Sep 23;3:58. PubMed.

    View all comments by Jean-Charles Lambert
  2. This study is a very interesting data set, one of the few that deals with potential mechanisms of tau propagation.

    BIN1 is the second-most-prevalent susceptibility gene for AD. It has been shown in a few studies in the past years that BIN1 seems to influence tau pathology (Chapuis et al., 2013). Also, strong evidence linked BIN1 as an active protein in membrane processes such as membrane curvature or clathrin-mediated endocytosis, particularly thanks to structural properties such as amphipathic helix/presence of an SH3 domain, presence of a CLAP domain, etc. These data lead the authors to hypothesize that BIN1 may be implicated in the propagation of tau proteins. In my opinion, they demonstrate this nicely, particularly showing that BIN1 overexpression reduces tau propagation while lowering intracellular levels of BIN1 increases tau propagation. The authors provide some mechanistic evidence, particularly showing that the CLAP domain is implicated in the observed effect or that this effect is probably mediated via an interaction of BIN1 with dynamin.

    We regret that no information is provided on three things: First, it is unclear from the charts provided whether the effect on tau propagation is total and if BIN1 is required in the tau propagation process or in the tau uptake via CME. Second, no information is provided on whether BIN1 directly impacts tau aggregation in their model in addition to CME. This data would be of interest as their models address tau transfer and seeding. Third, in their models the authors only see propagation of aggregates. What about propagation of soluble forms of tau, which has been demonstrated in many studies, including in vivo?

    Overall, this paper provides very interesting insights on tau propagation and now needs to be confirmed by other studies and in other models. In vivo data would be particularly interesting.

    References:

    . Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry. 2013 Feb 12; PubMed.

    View all comments by Simon Dujardin

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  1. Lack of BIN1 Sows Tau Trouble for Neurons