The Alzheimer's disease genetic risk factor BIN1 induces isoform-dependent neurotoxicity through early endosome defects

The Bridging Integrator 1 (BIN1) gene is a major genetic risk factor for Alzheimer's disease (AD) but little is known about its physiological functions. In addition, deciphering its potential pathophysiological role is difficult due to its numerous isoforms expressed in different cerebral cell types. Here we took advantage of a drosophila model to assess in vivo the impact of different BIN1 isoforms on neuronal toxicity: the neuronal isoform 1 (BIN1iso1), the muscular isoform 8 (BIN1iso8) and the ubiquituous isoform 9 (BIN1iso9). We showed that contrary to BIN1iso8 and BIN1iso9, BIN1iso1 overexpression induced neurodegeneration and an accumulation of vesicles mainly labeled by endosome markers. Systematic search for endosome trafficking regulators that are able to rescue BIN1iso1-induced neurodegeneration indicated a defect in the early endosome trafficking machinery. In human induced neurons and cerebral organoids, BIN1 knock-out resulted in narrowing of the early endosomes. This phenotype was rescued by BIN1iso1 expression but not that of BIN1iso9. Finally, in accordance with our previous observation in flies, we also observed that BIN1iso1 overexpression led to an increase in size of the early endosomes in human induced neurons. Altogether, our data demonstrate that the AD genetic risk factor BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation which is a very early pathophysiological feature observed in AD pathogenesis.

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ApoE4 attenuates cortical neuronal activity and impairs memory in young apoE4 rats

10.1101/2021.01.14.426651 ◽

2021 ◽

Author(s):

Ilona Har-Paz ◽

Elor Arieli ◽

Anan Moran

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Neuronal Activity ◽

Genetic Risk ◽

Cortical Neurons ◽

Late Onset ◽

Genetic Risk Factor ◽

Normal Brain ◽

Brain Functions

AbstractThe E4 allele of apolipoprotein E (apoE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). However, apoE4 may cause innate brain abnormalities before the appearance of AD related neuropathology. Understanding these primary dysfunctions is vital for early detection of AD and the development of therapeutic strategies for it. Recently we have shown impaired extra-hippocampal memory in young apoE4 mice – a deficit that was correlated with attenuated structural pre-synaptic plasticity in cortical and subcortical regions. Here we test the hypothesis that these early structural deficits impact learning via changes in basal and stimuli evoked neuronal activity. We recorded extracellular neuronal activity from the gustatory cortex (GC) of three-month-old humanized apoE4 and wildtype rats, before and after conditioned taste aversion (CTA) training. Despite normal sucrose drinking behavior before CTA, young apoE4 rats showed impaired CTA learning, consistent with our previous results in apoE4 mice. This behavioral deficit was correlated with decreased basal and taste-evoked firing rates in both putative excitatory and inhibitory GC neurons. Single neuron and ensemble analyses of taste coding demonstrated that apoE4 neurons could be used to correctly classify tastes, but were unable to undergo plasticity to support learning. Our results suggest that apoE4 impacts brain excitability and plasticity early in life and may act as an initiator for later AD pathologies.Significant statementThe ApoE4 allele is the strongest genetic risk-factor for late-onset Alzheimer’s disease (AD), yet the link between apoE4 and AD is still unclear. Recent molecular and in-vitro studies suggest that apoE4 interferes with normal brain functions decades before the development of its related AD neuropathology. Here we recorded the activity of cortical neurons from young apoE4 rats during extra-hippocampal learning to study early apoE4 neuronal activity abnormalities, and their effects over coding capacities. We show that apoE4 drastically reduces basal and stimuli-evoked cortical activity in both excitatory and inhibitory neurons. The apoE4-induced activity attenuation did not prevent coding of stimuli identity and valence, but impaired capacity to undergo activity changes to support learning. Our findings support the hypothesis that apoE4 interfere with normal neuronal plasticity early in life; a deficit that may lead to late-onset AD development.

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Pathological Synergism Between Amyloid-β and Apolipoprotein E4 – The Most Prevalent Yet Understudied Genetic Risk Factor for Alzheimer's Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-2009-1065 ◽

2009 ◽

Vol 17 (3) ◽

pp. 469-481 ◽

Cited By ~ 9

Author(s):

Haim Belinson ◽

Daniel M. Michaelson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Genetic Risk ◽

Amyloid Β ◽

Genetic Risk Factor ◽

Apolipoprotein E4

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Elucidating Molecular Phenotypes Caused by the SORL1 Alzheimer’s Disease Genetic Risk Factor Using Human Induced Pluripotent Stem Cells

Cell Stem Cell ◽

10.1016/j.stem.2015.02.004 ◽

2015 ◽

Vol 16 (4) ◽

pp. 373-385 ◽

Cited By ~ 89

Author(s):

Jessica E. Young ◽

Jonathan Boulanger-Weill ◽

Daniel A. Williams ◽

Grace Woodruff ◽

Floyd Buen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stem Cells ◽

Risk Factor ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Genetic Risk ◽

Genetic Risk Factor ◽

Induced Pluripotent ◽

Molecular Phenotypes

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The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01285-5 ◽

2022 ◽

Vol 10 (1) ◽

Author(s):

Erwan Lambert ◽

Orthis Saha ◽

Bruna Soares Landeira ◽

Ana Raquel Melo de Farias ◽

Xavier Hermant ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Susceptibility Gene ◽

Early Endosome ◽

Systematic Search ◽

Knock Out ◽

Early Endosomes ◽

Pathophysiological Role ◽

Induced Neurons ◽

Endosomal Vesicles

AbstractThe Bridging Integrator 1 (BIN1) gene is a major susceptibility gene for Alzheimer’s disease (AD). Deciphering its pathophysiological role is challenging due to its numerous isoforms. Here we observed in Drosophila that human BIN1 isoform1 (BIN1iso1) overexpression, contrary to human BIN1 isoform8 (BIN1iso8) and human BIN1 isoform9 (BIN1iso9), induced an accumulation of endosomal vesicles and neurodegeneration. Systematic search for endosome regulators able to prevent BIN1iso1-induced neurodegeneration indicated that a defect at the early endosome level is responsible for the neurodegeneration. In human induced neurons (hiNs) and cerebral organoids, BIN1 knock-out resulted in the narrowing of early endosomes. This phenotype was rescued by BIN1iso1 but not BIN1iso9 expression. Finally, BIN1iso1 overexpression also led to an increase in the size of early endosomes and neurodegeneration in hiNs. Altogether, our data demonstrate that the AD susceptibility gene BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation, which is an early pathophysiological hallmark of AD pathology.

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