Simoes S, Guo J, Buitrago L, Qureshi YH, Feng X, Kothiya M, Cortes E, Patel V, Kannan S, Kim YH, Chang KT, Alzheimer's Disease Neuroimaging Initiative, Hussaini SA, Moreno H, Di Paolo G, Andersen OM, Small SA. Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling. Cell Rep. 2021 Dec 28;37(13):110182. PubMed.

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  1. These reports from Scott Small and colleagues nicely underscore the underappreciated range of neural functions endosomes serve in trafficking and signaling within varied brain cell types. The studies add important new insight into how a depletion of Vps35 retromer can promote a range of AD-related phenotypes stemming from endosome dysfunction.

    From these and other studies, it has been increasingly appreciated that the endosome is subject to dysregulation from multiple directions in the AD brain, including (1) accelerated cargo entry and endosome fusion due to rab5 hyper-activation (Pensalfini et al., 2020); (2) deficient recycling from endosomes via rab11a- and Vps35/retromer routes, which impedes cargo exit and delivery to varied cellular sites (Woodruff et., 2016); and (3) back-up of cargo from compromised exosome production (Peng et al., 2019). Given the highly dynamic nature of early endosomes, it is expected that perturbing one of these entry or exit pathways of the endosome will alter activity of the others to maintain proper endosome size and function.

    The importance of the Vps35 retromer for endocytic processes in neurons is highlighted in Simoes et al., which uncovered an additional neuron-specific retromer assembly.

    Genetic influences driving early endosome dysfunction in AD neurons continue to be identified following the initial studies by Cataldo and colleagues linking the APOE4 allele to accelerated rab5-endosome enlargement in sporadic AD (Cataldo et al., 2000). Subsequently, early endosome dysfunction in Down’s syndrome was linked to APP via binding of APP- βCTF directly to the rab5-APPL1 complex on endosomes (Jiang et al., 2010; Kim et al., 2015).

    Recently, a substantial number of GWAS AD risk genes have further implicated endocytic dysfunction in AD pathogenesis, including inter-relationships that the Small group have described between retromer and SORL1, the deletion of which promotes rab5-endosome enlargement independently of an APP contribution (Knupp et al., 2020). Common to all these described mechanisms of AD-related endosome dysfunction is the swelling of early endosomes, the earliest known cellular anomaly specific to AD. This enlargement impairs endosome transport and neurotrophic signaling, leading to degeneration of cholinergic neurons, an early disease phenotype potentially responsive to the therapeutic modulation of rab5-endosome aberrant signaling (Salehi et al., 2006; Kim et al., 2015; Alam et al., CTAD 2021).

    The retromer analyses by Qureshi et al. clearly show that depletion of Vps35 induces, in addition to endosome swelling, varied neuronal dysfunctions associated with AD, including APP-CTF accumulation, GluA1 receptor reductions, and upregulation of glial markers. Notably, along with directly overactivating rab5 (Pensalfini et al., 2020), this is yet another example, of a highly selective perturbation of endosome function leading to a broad range of AD phenotypes independently from any stimulus needed from APP products.

    It will now be exciting to investigate whether it is possible to therapeutically modify either an entry or exit route of the early endosome to block the early onset of endosome swelling and aberrant signaling and its downstream consequences on synaptic function and neurotrophic signaling in AD and related dementias.

    References:

    Pensalfini A, Kim S, Subbanna S, Bleiwas C, Goulbourne CN, Stavrides PH, Jiang Y, Lee JH, Darji S, Pawlik M, Huo C, Peddy J, Berg MJ, Smiley JF, Basavarajappa BS, Nixon RA. Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer's Disease. Cell Rep. 2020 Nov 24;33(8):108420. PubMed.

    Woodruff G, Reyna SM, Dunlap M, Van Der Kant R, Callender JA, Young JE, Roberts EA, Goldstein LS. Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations. Cell Rep. 2016 Oct 11;17(3):759-773. PubMed.

    Peng KY, Pérez-González R, Alldred MJ, Goulbourne CN, Morales-Corraliza J, Saito M, Saito M, Ginsberg SD, Mathews PM, Levy E. Apolipoprotein E4 genotype compromises brain exosome production. Brain. 2019 Jan 1;142(1):163-175. PubMed.

    Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA. Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am J Pathol. 2000 Jul;157(1):277-86. PubMed.

    Jiang Y, Mullaney KA, Peterhoff CM, Che S, Schmidt SD, Boyer-Boiteau A, Ginsberg SD, Cataldo AM, Mathews PM, Nixon RA. Alzheimer's-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition. Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1630-5. Epub 2009 Dec 28 PubMed.

    Kim S, Sato Y, Mohan PS, Peterhoff C, Pensalfini A, Rigoglioso A, Jiang Y, Nixon RA. Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease. Mol Psychiatry. 2015 Jul 21; PubMed.

    Knupp A, Mishra S, Martinez R, Braggin JE, Szabo M, Kinoshita C, Hailey DW, Small SA, Jayadev S, Young JE. Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing. Cell Rep. 2020 Jun 2;31(9):107719. PubMed.

    Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC. Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron. 2006 Jul 6;51(1):29-42. PubMed.

    View all comments by Ralph Nixon

  2. Endosomal trafficking is essential in all cell types but certainly plays distinct roles in different cells. Retromer is a multiprotein complex that regulates multiple aspects of endosomal trafficking. Using elegant genetic approaches, Quershi et al. have shown that depletion of VPS35, a core component of retromer, recapitulates key AD neuropathoglogical and cytopathological phenotypes in hippocampal neurons. They also observe increases in activation of glial markers, such as GFAP and IBA1, and alterations in hippocampal microglial morphology, suggesting a non-cell autonomous effect of VPS35 deficiency. Repletion with VPS35 in neurons via a gene-therapy approach is able to normalize these phenotypes.

    Furthermore, and somewhat surprisingly, crossing the VPS35 deficient mice with tau knockout mice did not normalize microglial phenotypes, demonstrating that depletion of VPS35 is not dependent upon tau to induce either the neuronal or microglial phenotypes observed. This is further data supporting the hypothesis that endosomal/retromer dysfunction is a parallel, yet independent, driver of the AD disease process. One very promising aspect of this study is that it builds on work done in cell culture: first described in Mecozzi et al., 2014) and including our work (Young et al., 2018) to show that retromer can be a pharmacologic target.

    The study by Simoes and colleagues is the first to really dissect the separate function of two VPS26 paralogs, VPS26a and VPS26b, in neurons. VPS26 is part of the core component of retromer and while the existence of these paralogs was known, how they functionally behave was not. This study makes it clear that VPS26b is dedicated to endosomal recycling and that this is critical for normal neuronal function. In particular, VPS26b deficiency impacts the cell-surface recycling of the AMPAR subunit GLUA1, causing it to be trapped in early endosomes. This study also demonstrated that SORL1, an AD-associated gene with high pathogenicity, is reduced in VPS26b-deficient animals. SORL1 is an endosomal receptor that interacts with VPS26 in retromer-mediated trafficking and is also depleted in AD brains (confirmed here in Simoes et al.).

    This is very much in parallel with our recent work, currently on Biorxiv where we demonstrate that SORL1 deficiency in human-induced pluripotent stem cell derived neurons (hiPSC-Ns) also leads to trapped GLUA1 in endosomes, reduced GLUA1 on the cell surface, and altered neuronal function (Mishra et al., 2022). 

    Synaptic loss and dysfunction are early and defining phenotypes in AD—neurodegeneration is due to lack of functional synapases. This elegant study begins to suggest a mechanism by which retromer-dependent trafficking defects could contribute to this defining pathology.

    Together, these two studies highly implicate retromer-endosomal trafficking as a parallel driver of AD and provide proof-of-concept data suggesting that this could be a valid therapeutic target.

    References:

    Mecozzi VJ, Berman DE, Simoes S, Vetanovetz C, Awal MR, Patel VM, Schneider RT, Petsko GA, Ringe D, Small SA. Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol. 2014 Jun;10(6):443-9. Epub 2014 Apr 20 PubMed.

    Young JE, Fong LK, Frankowski H, Petsko GA, Small SA, Goldstein LS. Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein. Stem Cell Reports. 2018 Mar 13;10(3):1046-1058. Epub 2018 Mar 1 PubMed.

    Mishra S, Knupp A, Szabo MP, Williams CA, Kinoshita C, Hailey DW, Wang Y, Young JE. The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons. bioRxiv. January 11, 2022 BioRxiv.

    View all comments by Jessica Young

  3. These are two excellent studies that build on extensive prior work to further uncover how the retromer relates to AD-like phenotypes. Qureshi et al. show that neuronal knockout of the retromer component VPS35 leads not only to neuronal phenotypes seen in AD, including elevations in APP β-CTFs and loss of surface AMPA receptor subunit GluA1, but also increases in markers of astrocytes and microglia as well as an AD-like dystrophic microglia morphology in the hippocampus. Neuronal replacement of VPS35 via AAV viral vector delivery largely reversed these AD-like phenotypes. Interestingly, using tau-knockout mice, the authors show that these AD-like phenotypes induced by VPS35 deficiency are independent of tau. The study provides further evidence for crosstalk between neurons and glia, a growing topic of major interest in AD.

    Simoes et al. focus on the more brain-selective retromer component VPS26b as opposed to the more ubiquitous VPS26a. They show that knockdown of VPS26b in mice leads to selective fMRI alterations precisely in the early AD-vulnerable transentorhinal cortex. They then go on to show that VPS26b, but not VPS26a, heterozygous KO mice have impaired LTP as well as elevations in Aβ peptides in the entorhinal cortex; notably, their prior work suggested that VPS26a can also affect Aβ (Muhammad et al., 2008). Further, they show the importance of VPS26b in SORL1 and GluA1 recycling, and report marked loss of VPS26b and SORL1 in the entorhinal cortex in AD brain.

    All in all, this is an impressive amount of work, uncovering new biological insights into endosome dysfunction related to AD, as well as novel insights into the recycling of receptors important for learning and memory. Endosome-lysosome-autophagy dysfunction is heavily implicated in neurodegenerative diseases.

    Major questions that remain are why and how retromer biology is altered with age to promote AD. Genetics studies have pointed at retromer/endosome-related genes, and early onset familial AD gene mutations affect the endosome-lysosome system, but how dysfunction in endosomes develops with age in typical late-onset AD, without specific gene mutations linked to endosome biology, remains unclear.

    The authors describe the unique connectivity and anatomical pathways of the entorhinal cortex, but understanding how this sets the stage for AD to begin there requires more work. Of course, a pressing question, which I hope to hear more about in the coming years, is how the retromer might be targeted for AD therapy.

    At a more basic level, I wonder about the spatial localization of the two different VPS26 components to pre- versus post-synapses, and how precisely, at a subcellular level, retromer recycling is separated from transferrin recycling, given that retromer disruption was shown to alter GluA1 but not transferrin recycling (Temkin et al., 2017). Further, it will be interesting to define early retromer alterations in the specific neuron subtypes of the entorhinal cortex that are affected earliest in AD, such as reelin-positive layer II neurons (Kobro-Flatmoen et al., 2016).

    References:

    Muhammad A, Flores I, Zhang H, Yu R, Staniszewski A, Planel E, Herman M, Ho L, Kreber R, Honig LS, Ganetzky B, Duff K, Arancio O, Small SA. Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation. Proc Natl Acad Sci U S A. 2008 May 20;105(20):7327-32. PubMed.

    Temkin P, Morishita W, Goswami D, Arendt K, Chen L, Malenka R. The Retromer Supports AMPA Receptor Trafficking During LTP. Neuron. 2017 Apr 5;94(1):74-82.e5. PubMed.

    Kobro-Flatmoen A, Nagelhus A, Witter MP. Reelin-immunoreactive neurons in entorhinal cortex layer II selectively express intracellular amyloid in early Alzheimer's disease. Neurobiol Dis. 2016 Sep;93:172-83. Epub 2016 May 16 PubMed.

    View all comments by Gunnar Gouras

  4. The study by Qureshi and colleagues shows that retromer dysfunction in a specific population of neurons is related to synaptic deficits independent of AD-associated neuropathology. In this context, it is fascinating that neuronal deficit in VPS35 results in heightened [innate] immune response early in life. Some information about the functional changes that occur in microglia, concomitant with morphological changes, could direct more studies into how neuronal endosomal trafficking defects affect brain health through non-cell autonomous means, in the absence of AD neuropathology. So, this has some relevance to aging on a broader scale.

    Additionally, the link between VPS35 and APOE adds relevance to Alzheimer’s disease pathogenic cascade as well as to aging. Future work on the cellular source of APOE would be insightful (whether it is just a surrogate measure of increased astrocytosis or more a measure of CNS tissue damage).

    View all comments by Paramita Chakrabarty

  5. The paper by Simoes and colleagues provides fascinating data concerning regional brain differences in the function of endosomal trafficking regulators, which impact synaptic potentiation and memory in rodents and humans.

    The authors focus on the retromer subunit VPS26b, finding it enriched in neurons over other brain cells, and increased in a relatively small brain region, the transentorhinal cortex. They demonstrate that VPS26b knockout causes LTP defects in the TEC but not in the medial entorhinal cortex (MEC). Moreover, the study proposes that VPS26b affects LTP via the recycling of GluA1, the glutamatergic AMPA receptor required for LTP maintenance.

    In addition, VPS26b KO, like VPS35, another retromer subunit, increases Aβ levels and CSF tau with aging.

    The paper is complete, going from cell biology to mice physiology and behavior and human brain imaging. One is left wondering why the TEC is such a vulnerable area compared to other essential regions in AD, such as the CA1 area, where, given the abundance of GluA1, one would expect its trafficking to be under even tighter control.

    View all comments by Claudia Almeida

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