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A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease A? production.

ABSTRACT: Abnormal accumulation of ?-secretase (BACE1) in dystrophic neurites and presynaptic ?-amyloid (A?) production contribute to Alzheimer's disease pathogenesis. Little, however, is known about BACE1 sorting and dynamic transport in neurons. We investigated BACE1 trafficking in hippocampal neurons using live-cell imaging and selective labeling. We report that transport vesicles containing internalized BACE1 in dendrites undergo exclusive retrograde transport toward the soma, whereas they undergo bidirectional transport in axons. Unidirectional dendritic transport requires Eps15-homology-domain-containing (EHD) 1 and 3 protein function. Furthermore, loss of EHD function compromises dynamic axonal transport and overall BACE1 levels in axons. EHD1/3 colocalize with BACE1 and APP ?-C-terminal fragments in hippocampal mossy fiber terminals, and their depletion in neurons significantly attenuates A? levels. These results demonstrate unidirectional endocytic transport of a dendritic cargo and reveal a role for EHD proteins in neuronal BACE1 transcytosis and A? production, processes that are highly relevant for Alzheimer's disease.

SUBMITTER: Buggia-Prevot V

PROVIDER: S-EPMC3932704 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease Aβ production.

Buggia-Prévot Virginie V Fernandez Celia G CG Udayar Vinod V Vetrivel Kulandaivelu S KS Elie Aureliane A Roseman Jelita J Sasse Verena A VA Lefkow Margaret M Meckler Xavier X Bhattacharyya Sohinee S George Manju M Kar Satyabrata S Bindokas Vytautas P VP Parent Angèle T AT Rajendran Lawrence L Band Hamid H Vassar Robert R Thinakaran Gopal G

Cell reports 20131201 6

Abnormal accumulation of β-secretase (BACE1) in dystrophic neurites and presynaptic β-amyloid (Aβ) production contribute to Alzheimer's disease pathogenesis. Little, however, is known about BACE1 sorting and dynamic transport in neurons. We investigated BACE1 trafficking in hippocampal neurons using live-cell imaging and selective labeling. We report that transport vesicles containing internalized BACE1 in dendrites undergo exclusive retrograde transport toward the soma, whereas they undergo bid ...[more]

PMID: 24373286

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Project description:Amyloid-? (A?) peptides play a key role in synaptic damage and memory deficits in the early pathogenesis of Alzheimer's disease (AD). Abnormal accumulation of A? at nerve terminals leads to synaptic pathology and ultimately to neurodegeneration. ?-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal ?-secretase for A? generation. However, the mechanisms regulating BACE1 distribution in axons and ? cleavage of APP at synapses remain largely unknown. Here, we reveal that dynein-Snapin-mediated retrograde transport regulates BACE1 trafficking in axons and APP processing at presynaptic terminals. BACE1 is predominantly accumulated within late endosomes at the synapses of AD-related mutant human APP (hAPP) transgenic (Tg) mice and patient brains. Defective retrograde transport by genetic ablation of snapin in mice recapitulates late endocytic retention of BACE1 and increased APP processing at presynaptic sites. Conversely, overexpressing Snapin facilitates BACE1 trafficking and reduces synaptic BACE1 accumulation by enhancing the removal of BACE1 from distal AD axons and presynaptic terminals. Moreover, elevated Snapin expression via stereotactic hippocampal injections of adeno-associated virus particles in mutant hAPP Tg mouse brains decreases synaptic A? levels and ameliorates synapse loss, thus rescuing cognitive impairments associated with hAPP mice. Altogether, our study provides new mechanistic insights into the complex regulation of BACE1 trafficking and presynaptic localization through Snapin-mediated dynein-driven retrograde axonal transport, thereby suggesting a potential approach of modulating A? levels and attenuating synaptic deficits in AD.SIGNIFICANCE STATEMENT ?-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) trafficking and synaptic localization significantly influence its ? secretase activity and amyloid-? (A?) production. In AD brains, BACE1 is accumulated within dystrophic neurites, which is thought to augment A?-induced synaptotoxicity by A? overproduction. However, it remains largely unknown whether axonal transport regulates synaptic APP processing. Here, we demonstrate that Snapin-mediated retrograde transport plays a critical role in removing BACE1 from presynaptic terminals toward the soma, thus reducing synaptic A? production. Adeno-associated virus-mediated Snapin overexpression in the hippocampus of mutant hAPP mice significantly decreases synaptic A? levels, attenuates synapse loss, and thus rescues cognitive deficits. Our study uncovers a new pathway that controls synaptic APP processing by enhancing axonal BACE1 trafficking, thereby advancing our fundamental knowledge critical for ameliorating A?-linked synaptic pathology.

Project description:Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aβ, particularly neurotoxic Aβ42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aβ42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aβ generation. Our study supports the hypothesis that Aβ induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of BACE1 and exacerbation of amyloid pathology in AD.

Dataset Information

A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease A? production.

Publications

A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease Aβ production.

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