Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate A\u03b2 production

Viktoriya Zhuravleva,Ioannis Sotiropoulos,Nuno Sousa,Joana M Silva,João Vaz-Silva,Patricia Gomes,Clarissa L Waites,Mei Zhu

doi:10.1038/s41419-021-04433-w

Viktoriya Zhuravleva, Ioannis Sotiropoulos + Show 6 more

Open Access

https://doi.org/10.1038/s41419-021-04433-w

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Abstract

Chronic stress and elevated glucocorticoids (GCs), the major stress hormones, are risk factors for Alzheimer’s disease (AD) and promote AD pathomechanisms, including overproduction of toxic amyloid-β (Aβ) peptides and intraneuronal accumulation of hyperphosphorylated Tau protein. The latter is linked to downregulation of the small GTPase Rab35, which mediates Tau degradation via the endolysosomal pathway. Whether Rab35 is also involved in Aβ overproduction remains an open question. Here, we find that hippocampal Rab35 levels are decreased not only by stress/GC but also by aging, another AD risk factor. Moreover, we show that Rab35 negatively regulates Aβ production by sorting amyloid precursor protein (APP) and β-secretase (BACE1) out of the endosomal network, where they interact to produce Aβ. Interestingly, Rab35 coordinates distinct intracellular trafficking steps for BACE1 and APP, mediated by its effectors OCRL and ACAP2, respectively. Finally, we demonstrate that Rab35 overexpression prevents the amyloidogenic trafficking of APP and BACE1 induced by high GC levels. These studies identify Rab35 as a key regulator of APP processing and suggest that its downregulation may contribute to stress-related and AD-related amyloidogenesis.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disease and cause of dementia
We previously found that Rab35 mediates Tau degradation via the endolysosomal pathway, and that its GC-driven transcriptional suppression leads to Tau accumulation in the hippocampus, inducing synaptic loss and dendritic atrophy [10]
We show for the first time that Rab35 regulates amyloid precursor protein (APP) and BACE1 trafficking (Fig. 7), and that its suppression by GCs leads to increased interaction between APP and BACE1 within the endosomal network, likely facilitating Aβ overproduction

Summary

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disease and cause of dementia. Recent work has shown that chronic unpredictable stress and high GC levels induce AD-like pathology in animal models, including the overproduction of toxic amyloid-beta (Aβ) peptides, as well as the accumulation, hyperphosphorylation, and synaptic missorting of Tau protein, leading to synaptotoxicity and memory impairment [4,5,6,7,8,9]. AAV-mediated overexpression of Rab in the rodent hippocampus was sufficient to prevent GC-induced Tau accumulation and downstream dendrite and spine loss [10]. These findings demonstrate that GCs precipitate Tau pathology by disrupting Rab35-mediated endolysosomal trafficking. Given that Rab mediates multiple other intracellular trafficking events, including the retrograde trafficking of mannose-6-phosphate receptors [11] and the recycling of cell-surface receptors and adhesion molecules [12,13,14], its GC-mediated downregulation could impact amyloid precursor protein (APP) trafficking and contribute to stressinduced Aβ production

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