Dataset Information

Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease.

ABSTRACT: Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear whether glymphatic transport affects the distribution of soluble A? in Alzheimer's disease (AD). In wild type mice, we show that A?40 (fluorescently labeled A?40 or unlabeled A?40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, A?42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to A?40. Interestingly, pretreatment with A?40 in the CSF, but not A?42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-? deposits, glymphatic transport was reduced, due to the accumulation of toxic A? species, such as soluble oligomers. CSF-derived A?40 co-localizes with existing endogenous vascular and parenchymal amyloid-? plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal A? accumulation. Importantly, glymphatic failure preceded significant amyloid-? deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD.

SUBMITTER: Peng W

PROVIDER: S-EPMC4980916 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease.

Peng Weiguo W Achariyar Thiyagarajan M TM Li Baoman B Liao Yonghong Y Mestre Humberto H Hitomi Emi E Regan Sean S Kasper Tristan T Peng Sisi S Ding Fengfei F Benveniste Helene H Nedergaard Maiken M Deane Rashid R

Neurobiology of disease 20160524

Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear whether glymphatic transport affects the distribution of soluble Aβ in Alzheimer's disease (AD). In wild type mice, we show that Aβ40 (fluorescently labeled Aβ40 or unlabeled Aβ40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Aβ42 was mostly restricted ...[more]

PMID: 27234656

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Project description:Amyloid-β (Aβ) peptides play a key role in synaptic damage and memory deficits in the early pathogenesis of Alzheimer's disease (AD). Abnormal accumulation of Aβ at nerve terminals leads to synaptic pathology and ultimately to neurodegeneration. β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal β-secretase for Aβ generation. However, the mechanisms regulating BACE1 distribution in axons and β 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 Aβ 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 Aβ levels and attenuating synaptic deficits in AD.SIGNIFICANCE STATEMENT β-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) trafficking and synaptic localization significantly influence its β secretase activity and amyloid-β (Aβ) production. In AD brains, BACE1 is accumulated within dystrophic neurites, which is thought to augment Aβ-induced synaptotoxicity by Aβ 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 Aβ production. Adeno-associated virus-mediated Snapin overexpression in the hippocampus of mutant hAPP mice significantly decreases synaptic Aβ 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 Aβ-linked synaptic pathology.

Dataset Information

Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease.

Publications

Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease.

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