Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling

Simoes, Sabrina; Guo, Jia; Buitrago, Luna; Qureshi, Yasir H.; Feng, Xinyang; Kothiya, Milankumar; Cortés, Etty; Patel, Vivek M.; Kannan, Suvarnambiga; Kim, Younghyun; Chang, Kyu‐Tae; Moreno, Herman; Andersen, Olav M.; Small, Scott A.

doi:10.1016/j.celrep.2021.110182

Cited by 41 publications

(68 citation statements)

References 77 publications

(131 reference statements)

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“…8 . In general, our results in human neurons corroborate studies in other cellular and animal models that implicate SORL1 as a key player in endosomal trafficking and recycling [ 1 , 22 , 31 , 63 , 82 ]. However, our study has certain limitations.…”

Section: Discussionsupporting

confidence: 89%

“…5 ). This finding is critically important as recent work indicates that in mouse cortical neurons, SORLA interacts with a neuronal specific retromer subunit, VPS26b, to promote recycling of glutamate receptors [ 80 ]. In our cortical neurons when SORL1 is depleted, there is a reduction of GLUA1 subunits on the cell surface and this may result in synaptic impairment.…”

Section: Discussionmentioning

confidence: 99%

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The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons

Mishra

Knupp

Szabo

et al. 2022

Cell. Mol. Life Sci.

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Background Loss of the Sortilin-related receptor 1 (SORL1) gene seems to act as a causal event for Alzheimer’s disease (AD). Recent studies have established that loss of SORL1, as well as mutations in autosomal dominant AD genes APP and PSEN1/2, pathogenically converge by swelling early endosomes, AD’s cytopathological hallmark. Acting together with the retromer trafficking complex, SORL1 has been shown to regulate the recycling of the amyloid precursor protein (APP) out of the endosome, contributing to endosomal swelling and to APP misprocessing. We hypothesized that SORL1 plays a broader role in neuronal endosomal recycling and used human induced pluripotent stem cell-derived neurons (hiPSC-Ns) to test this hypothesis. We examined endosomal recycling of three transmembrane proteins linked to AD pathophysiology: APP, the BDNF receptor Tropomyosin-related kinase B (TRKB), and the glutamate receptor subunit AMPA1 (GLUA1). Methods We used isogenic hiPSCs engineered to have SORL1 depleted or to have enhanced SORL1 expression. We differentiated neurons from these cell lines and mapped the trafficking of APP, TRKB and GLUA1 within the endosomal network using confocal microscopy. We also performed cell surface recycling and lysosomal degradation assays to assess the functionality of the endosomal network in both SORL1-depleted and -overexpressing neurons. The functional impact of GLUA1 recycling was determined by measuring synaptic activity. Finally, we analyzed alterations in gene expression in SORL1-depleted neurons using RNA sequencing. Results We find that as with APP, endosomal trafficking of GLUA1 and TRKB is impaired by loss of SORL1. We show that trafficking of all three cargoes to late endosomes and lysosomes is affected by manipulating SORL1 expression. We also show that depletion of SORL1 significantly impacts the endosomal recycling pathway for APP and GLUA1 at the level of the recycling endosome and trafficking to the cell surface. This has a functional effect on neuronal activity as shown by multi-electrode array (MEA). Conversely, increased SORL1 expression enhances endosomal recycling for APP and GLUA1. Our unbiased transcriptomic data further support SORL1’s role in endosomal recycling. We observe altered expression networks that regulate cell surface trafficking and neurotrophic signaling in SORL1-depleted neurons. Conclusion Collectively, and together with other recent observations, these findings suggest that one role for SORL1 is to contribute to endosomal degradation and recycling pathways in neurons, a conclusion that has both pathogenic and therapeutic implications for Alzheimer’s disease.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons

Mishra

Knupp

Szabo

et al. 2022

Cell. Mol. Life Sci.

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“…Similar to the above approach, we performed a VBA analysis over the hippocampal circuit (Figure 4A). Replicating previous findings (Braak and Braak, 1996;Brickman et al, 2011Brickman et al, , 2014Small et al, 2011;Pavlopoulos et al, 2013;Schobel et al, 2013;Khan et al, 2014;Sperling et al, 2014;Coughlan et al, 2018;Provenzano et al, 2020;Simoes et al, 2021), the Alzheimer's disease-related decline in the synthesized CBV maps primarily localized to a region termed the transentorhinal cortex (TEC) ( Figures 4E,F). In the complementary ROI analysis of the right TEC, the synthesized CBV values were significantly .…”

Section: Alzheimer's Diseasesupporting

confidence: 85%

Deep learning of MRI contrast enhancement for mapping cerebral blood volume from single-modal non-contrast scans of aging and Alzheimer's disease brains

Liu

Zhu

Sun

et al. 2022

Front. Aging Neurosci.

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While MRI contrast agents such as those based on Gadolinium are needed for high-resolution mapping of brain metabolism, these contrast agents require intravenous administration, and there are rising concerns over their safety and invasiveness. Furthermore, non-contrast MRI scans are more commonly performed than those with contrast agents and are readily available for analysis in public databases such as the Alzheimer's Disease Neuroimaging Initiative (ADNI). In this article, we hypothesize that a deep learning model, trained using quantitative steady-state contrast-enhanced structural MRI datasets, in mice and humans, can generate contrast-equivalent information from a single non-contrast MRI scan. The model was first trained, optimized, and validated in mice, and was then transferred and adapted to humans. We observe that the model can substitute for Gadolinium-based contrast agents in approximating cerebral blood volume, a quantitative representation of brain activity, at sub-millimeter granularity. Furthermore, we validate the use of our deep-learned prediction maps to identify functional abnormalities in the aging brain using locally obtained MRI scans, and in the brain of patients with Alzheimer's disease using publicly available MRI scans from ADNI. Since it is derived from a commonly-acquired MRI protocol, this framework has the potential for broad clinical utility and can also be applied retrospectively to research scans across a host of neurological/functional diseases.

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“…4k and Supplementary Data 10) 30 . Retromer dysfunction has been associated with age-related neurodegenerative diseases that are protected by DR, including AD [31][32][33][34] , especially in tra cking cargo involved in disease progression 21 . We therefore also analyzed human OXR1 and retromer-associated protein abundance using the AMP-AD dataset 35 .…”

Section: Mtd/oxr1 Expression Protects Against Neurodegenerative Disea...mentioning

confidence: 99%

OXR1 maintains the retromer to delay brain aging under dietary restriction

Kapahi

Wilson

Bar

et al. 2022

Preprint

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Dietary restriction (DR) delays aging and neurodegeneration, but the mechanisms behind this remain to be elucidated. We identified genetic polymorphisms in mustard (mtd), the fly homolog of Oxidation resistance 1 (OXR1), which influenced lifespan and mtd expression in neurons in response to DR regulated by the transcription factor Traffic jam (TJ). Knockdown of mtd inhibited DR-mediated lifespan extension. We found that mtd expression naturally declines with age and that loss of mtd destabilized the retromer complex, which regulates trafficking and reuse of endocytosed proteins and lipids and maintains proper lysosomal function. Overexpression of retromer genes Vps35 or Vps26 or pharmacological restabilization with the compound R55 rescued lifespan and neurodegeneration in mtd-deficient flies as well as lysosomal defects in cells from patients who suffer from rapid neurological degeneration caused by loss-of-function of OXR1 variants. Multi-omic analyses in flies and humans showed that decreased Mtd/OXR1 associates with aging and multiple neurological diseases, including Alzheimer’s disease, and its overexpression rescued age-related visual decline and tauopathy in a fly model. Hence, OXR1 plays a conserved role in enhancing retromer function and is critical for neuronal health and longevity across species.

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Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling

Cited by 41 publications

References 77 publications

The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons

The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons

Deep learning of MRI contrast enhancement for mapping cerebral blood volume from single-modal non-contrast scans of aging and Alzheimer's disease brains

OXR1 maintains the retromer to delay brain aging under dietary restriction

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