Loss of endophilin-B1 exacerbates Alzheimer's disease pathology

David B. Wang, Yoshito Kinoshita, Chizuru Kinoshita, Takuma Uo, Bryce L. Sopher, Eiron Cudaback, C. Dirk Keene, Tina Bilousova, Karen Gylys, Amanda Case, Suman Jayadev, Hong-Gang Wang, Gwenn A. Garden, Richard S. Morrison

Research output: Contribution to journalArticle

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Abstract

Endophilin-B1, also known as Bax-interacting factor 1 (Bif-1, and encoded by SH3GLB1), is a multifunctional protein involved in apoptosis, autophagy and mitochondrial function. We recently described a unique neuroprotective role for neuron-specific alternatively spliced isoforms of endophilin-B1. To examine whether endophilin-B1-mediated neuroprotection could be a novel therapeutic target for Alzheimer's disease we used a double mutant amyloid precursor protein and presenilin 1 (APPswe/PSEN1dE9) mouse model of Alzheimer's disease and observed that expression of neuron-specific endophilin-B1 isoforms declined with disease progression. To determine if this reduction in endophilin-B1 has a functional role in Alzheimer's disease pathogenesis, we crossed endophilin-B1-/- mice with APPswe/PSEN1dE9 mice. Deletion of endophilin-B1 accelerated disease onset and progression in 6-month-old APPswe/PSEN1dE9/endophilin-B1-/- mice, which showed more plaques, astrogliosis, synaptic degeneration, cognitive impairment and mortality than APPswe/PSEN1dE9 mice. In mouse primary cortical neuron cultures, overexpression of neuron-specific endophilin-B1 isoforms protected against amyloid-β-induced apoptosis and mitochondrial dysfunction. Additionally, protein and mRNA levels of neuron-specific endophilin-B1 isoforms were also selectively decreased in the cerebral cortex and in the synaptic compartment of patients with Alzheimer's disease. Flow sorting of synaptosomes from patients with Alzheimer's disease demonstrated a negative correlation between amyloid-β and endophilin-B1 levels. The importance of endophilin-B1 in neuronal function was further underscored by the development of synaptic degeneration and cognitive and motor impairment in endophilin-B1-/- mice by 12 months. Our findings suggest that endophilin-B1 is a key mediator of a feed-forward mechanism of Alzheimer's disease pathogenesis where amyloid-β reduces neuron-specific endophilin-B1, which in turn enhances amyloid-β accumulation and neuronal vulnerability to stress.

Original languageEnglish (US)
Pages (from-to)2005-2019
Number of pages15
JournalBrain
Volume138
Issue number7
DOIs
StatePublished - Jul 1 2015

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Alzheimer Disease
Amyloid
Pathology
Neurons
Protein Isoforms
Disease Progression
Apoptosis
Presenilin-1
Synaptosomes
Autophagy
Mutant Proteins
Cerebral Cortex
Proteins
Messenger RNA
Mortality
Cognitive Dysfunction

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Wang, D. B., Kinoshita, Y., Kinoshita, C., Uo, T., Sopher, B. L., Cudaback, E., ... Morrison, R. S. (2015). Loss of endophilin-B1 exacerbates Alzheimer's disease pathology. Brain, 138(7), 2005-2019. https://doi.org/10.1093/brain/awv128
Wang, David B. ; Kinoshita, Yoshito ; Kinoshita, Chizuru ; Uo, Takuma ; Sopher, Bryce L. ; Cudaback, Eiron ; Keene, C. Dirk ; Bilousova, Tina ; Gylys, Karen ; Case, Amanda ; Jayadev, Suman ; Wang, Hong-Gang ; Garden, Gwenn A. ; Morrison, Richard S. / Loss of endophilin-B1 exacerbates Alzheimer's disease pathology. In: Brain. 2015 ; Vol. 138, No. 7. pp. 2005-2019.
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abstract = "Endophilin-B1, also known as Bax-interacting factor 1 (Bif-1, and encoded by SH3GLB1), is a multifunctional protein involved in apoptosis, autophagy and mitochondrial function. We recently described a unique neuroprotective role for neuron-specific alternatively spliced isoforms of endophilin-B1. To examine whether endophilin-B1-mediated neuroprotection could be a novel therapeutic target for Alzheimer's disease we used a double mutant amyloid precursor protein and presenilin 1 (APPswe/PSEN1dE9) mouse model of Alzheimer's disease and observed that expression of neuron-specific endophilin-B1 isoforms declined with disease progression. To determine if this reduction in endophilin-B1 has a functional role in Alzheimer's disease pathogenesis, we crossed endophilin-B1-/- mice with APPswe/PSEN1dE9 mice. Deletion of endophilin-B1 accelerated disease onset and progression in 6-month-old APPswe/PSEN1dE9/endophilin-B1-/- mice, which showed more plaques, astrogliosis, synaptic degeneration, cognitive impairment and mortality than APPswe/PSEN1dE9 mice. In mouse primary cortical neuron cultures, overexpression of neuron-specific endophilin-B1 isoforms protected against amyloid-β-induced apoptosis and mitochondrial dysfunction. Additionally, protein and mRNA levels of neuron-specific endophilin-B1 isoforms were also selectively decreased in the cerebral cortex and in the synaptic compartment of patients with Alzheimer's disease. Flow sorting of synaptosomes from patients with Alzheimer's disease demonstrated a negative correlation between amyloid-β and endophilin-B1 levels. The importance of endophilin-B1 in neuronal function was further underscored by the development of synaptic degeneration and cognitive and motor impairment in endophilin-B1-/- mice by 12 months. Our findings suggest that endophilin-B1 is a key mediator of a feed-forward mechanism of Alzheimer's disease pathogenesis where amyloid-β reduces neuron-specific endophilin-B1, which in turn enhances amyloid-β accumulation and neuronal vulnerability to stress.",
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Wang, DB, Kinoshita, Y, Kinoshita, C, Uo, T, Sopher, BL, Cudaback, E, Keene, CD, Bilousova, T, Gylys, K, Case, A, Jayadev, S, Wang, H-G, Garden, GA & Morrison, RS 2015, 'Loss of endophilin-B1 exacerbates Alzheimer's disease pathology', Brain, vol. 138, no. 7, pp. 2005-2019. https://doi.org/10.1093/brain/awv128

Loss of endophilin-B1 exacerbates Alzheimer's disease pathology. / Wang, David B.; Kinoshita, Yoshito; Kinoshita, Chizuru; Uo, Takuma; Sopher, Bryce L.; Cudaback, Eiron; Keene, C. Dirk; Bilousova, Tina; Gylys, Karen; Case, Amanda; Jayadev, Suman; Wang, Hong-Gang; Garden, Gwenn A.; Morrison, Richard S.

In: Brain, Vol. 138, No. 7, 01.07.2015, p. 2005-2019.

Research output: Contribution to journalArticle

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AU - Wang, David B.

AU - Kinoshita, Yoshito

AU - Kinoshita, Chizuru

AU - Uo, Takuma

AU - Sopher, Bryce L.

AU - Cudaback, Eiron

AU - Keene, C. Dirk

AU - Bilousova, Tina

AU - Gylys, Karen

AU - Case, Amanda

AU - Jayadev, Suman

AU - Wang, Hong-Gang

AU - Garden, Gwenn A.

AU - Morrison, Richard S.

PY - 2015/7/1

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N2 - Endophilin-B1, also known as Bax-interacting factor 1 (Bif-1, and encoded by SH3GLB1), is a multifunctional protein involved in apoptosis, autophagy and mitochondrial function. We recently described a unique neuroprotective role for neuron-specific alternatively spliced isoforms of endophilin-B1. To examine whether endophilin-B1-mediated neuroprotection could be a novel therapeutic target for Alzheimer's disease we used a double mutant amyloid precursor protein and presenilin 1 (APPswe/PSEN1dE9) mouse model of Alzheimer's disease and observed that expression of neuron-specific endophilin-B1 isoforms declined with disease progression. To determine if this reduction in endophilin-B1 has a functional role in Alzheimer's disease pathogenesis, we crossed endophilin-B1-/- mice with APPswe/PSEN1dE9 mice. Deletion of endophilin-B1 accelerated disease onset and progression in 6-month-old APPswe/PSEN1dE9/endophilin-B1-/- mice, which showed more plaques, astrogliosis, synaptic degeneration, cognitive impairment and mortality than APPswe/PSEN1dE9 mice. In mouse primary cortical neuron cultures, overexpression of neuron-specific endophilin-B1 isoforms protected against amyloid-β-induced apoptosis and mitochondrial dysfunction. Additionally, protein and mRNA levels of neuron-specific endophilin-B1 isoforms were also selectively decreased in the cerebral cortex and in the synaptic compartment of patients with Alzheimer's disease. Flow sorting of synaptosomes from patients with Alzheimer's disease demonstrated a negative correlation between amyloid-β and endophilin-B1 levels. The importance of endophilin-B1 in neuronal function was further underscored by the development of synaptic degeneration and cognitive and motor impairment in endophilin-B1-/- mice by 12 months. Our findings suggest that endophilin-B1 is a key mediator of a feed-forward mechanism of Alzheimer's disease pathogenesis where amyloid-β reduces neuron-specific endophilin-B1, which in turn enhances amyloid-β accumulation and neuronal vulnerability to stress.

AB - Endophilin-B1, also known as Bax-interacting factor 1 (Bif-1, and encoded by SH3GLB1), is a multifunctional protein involved in apoptosis, autophagy and mitochondrial function. We recently described a unique neuroprotective role for neuron-specific alternatively spliced isoforms of endophilin-B1. To examine whether endophilin-B1-mediated neuroprotection could be a novel therapeutic target for Alzheimer's disease we used a double mutant amyloid precursor protein and presenilin 1 (APPswe/PSEN1dE9) mouse model of Alzheimer's disease and observed that expression of neuron-specific endophilin-B1 isoforms declined with disease progression. To determine if this reduction in endophilin-B1 has a functional role in Alzheimer's disease pathogenesis, we crossed endophilin-B1-/- mice with APPswe/PSEN1dE9 mice. Deletion of endophilin-B1 accelerated disease onset and progression in 6-month-old APPswe/PSEN1dE9/endophilin-B1-/- mice, which showed more plaques, astrogliosis, synaptic degeneration, cognitive impairment and mortality than APPswe/PSEN1dE9 mice. In mouse primary cortical neuron cultures, overexpression of neuron-specific endophilin-B1 isoforms protected against amyloid-β-induced apoptosis and mitochondrial dysfunction. Additionally, protein and mRNA levels of neuron-specific endophilin-B1 isoforms were also selectively decreased in the cerebral cortex and in the synaptic compartment of patients with Alzheimer's disease. Flow sorting of synaptosomes from patients with Alzheimer's disease demonstrated a negative correlation between amyloid-β and endophilin-B1 levels. The importance of endophilin-B1 in neuronal function was further underscored by the development of synaptic degeneration and cognitive and motor impairment in endophilin-B1-/- mice by 12 months. Our findings suggest that endophilin-B1 is a key mediator of a feed-forward mechanism of Alzheimer's disease pathogenesis where amyloid-β reduces neuron-specific endophilin-B1, which in turn enhances amyloid-β accumulation and neuronal vulnerability to stress.

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Wang DB, Kinoshita Y, Kinoshita C, Uo T, Sopher BL, Cudaback E et al. Loss of endophilin-B1 exacerbates Alzheimer's disease pathology. Brain. 2015 Jul 1;138(7):2005-2019. https://doi.org/10.1093/brain/awv128