In two recent Cell Reports papers, scientists led by Scott Small, Columbia University, New York, detail new insights into the function of the retromer, an endosome protein complex linked to Alzheimer’s disease. In one, published December 28 last year, first author Sabrina Simoes and colleagues reported that neurons rely on vacuolar protein sorting ortholog 26b (VPS26b), a retromer component. Knocking it out in mice slowed glutamate receptor recycling and weakened synaptic transmission, but only in the transentorhinal cortex, hinting at why this region is so vulnerable to AD pathology in people. In the January 18 issue, Small, Beth Stevens at Boston Children’s Hospital, and colleagues reported that knocking out a different retromer protein, VPS35, in hippocampal neurons in mice not only jammed neuronal endosome traffic but also caused microglia to assume shapes resembling those seen in AD. Adding VPS35 back into the neurons restored both protein trafficking and microglial morphology. Together, these papers support the idea that retromer dysfunction could set the stage for cellular changes seen in AD.

  • The retromer subunit VPS26b seems crucial for neurons.
  • Mouse VPS26b knockouts had more Aβ, less entorhinal cortex neurotransmission, and worse memory function.
  • Transentorhinal cortex from AD cases was deficient in VPS26b.
  • Retromer loss evoked AD-like dysmorphic microglia.

“These two reports nicely underscore the underappreciated range of neural functions that endosomes serve in trafficking and signaling,” Ralph Nixon, New York University, Orangeburg, wrote to Alzforum. Jessica Young, University of Washington, Seattle, agreed. “These papers show that endosomal-dependent recycling is crucial for maintaining synaptic function, which is incredibly important in the context of neurodegeneration,” she told Alzforum (full comments below).

Double Duty
The core of the retromer complex, comprising VPS26, VPS29, and VPS35, shuttles endosomal cargo for recycling either through the trans-Golgi network or directly back to the cell surface (see image at right and Kovtun et al., 2018). Every cell in the body contains the protein triad, but the brain boasts two versions of VPS26—VPS26a and VPS26b (Burgarcic et al., 2011). 

Two’s Not Company. In cultured primary neurons from mice, fluorescent antibodies to VPS26a (blue) and 26b (red) detected two distinct retromer complexes. Each protein co-localized with VPS35 (not shown). [Courtesy of Simoes et al., Cell Reports, 2021.]

To see which brain cells carried which VPS26, Simoes cultured primary mouse neurons, astrocytes, microglia, and endothelial cells separately. Western blotting showed VPS26b enriched only within neurons. Confocal microscopy of the neurons using antibodies against each VPS26 isoform showed distinct puncta, indicating two separate retromer triads.

Could these two distinct cores serve distinct functions? Simoes found VPS26a co-localized with markers of all three types of endosomes—early, late, and recycling—while VPS26b associated primarily with early and recycling endosomes. The latter facilitate neurotransmission by transporting internalized neurotransmitter receptors back to the synapse surface. After stimulating long-term potentiation (LTP) to strengthen synaptic signaling, VPS26b flocked to recycling endosomes (see image above right). To the authors, this suggested that VPS26b is essential for endosome recycling, especially during synaptic signaling, and that neurons carry this secondary retromer core to handle the high receptor recycling load.

To probe VPS26b's role in brain function, the scientists turned to VPS26b knockout mice. Using high-resolution functional MRI, the authors found the tiny transentorhinal cortex lit up more in 3-month-old knockouts than it did in age-matched wild-type controls (see image below). In contrast, 12-month-old knockouts had less metabolic activity than controls in the same region. “We’ve never seen such a clean fMRI image, especially after knocking out just one gene,” Small told Alzforum.

Divide and Conquer. In neurons, the retromers containing VPS26a (blue) mainly facilitate trafficking to the trans-Golgi network, while those containing VPS26b (orange) recycle receptors, such as GluA1, back to the cell surface. [Courtesy of Simoes et al., Cell Reports, 2021.]

The transentorhinal cortex acts as a synaptic trafficking hub for the entire cortex, requiring efficient endosomal recycling to maintain cell-surface glutamate-receptor levels (Choy et al., 2014; Temkin et al., 2017). Given the metabolic decline in the 12-month-old VPS26b knockouts, did synaptic signaling wane as well? Indeed, LTP weakened and glutamate receptor GluA1 expression was lower in TEC brain slices, while both were normal in the medial entorhinal cortex. Intriguingly, LTP was normal in TEC slices from heterozygous knockouts of the alternate VPS26a subunit, whereas homozygous VPS26a knockouts died in utero. Taken together, the authors concluded that the TEC relies on the VPS26b form of the retromer complex for proper synapse signaling.

Spot On. Compared to wild-type mice (gray), young Vps26b knockouts (red) had higher cerebral blood volume, a proxy for metabolic activity, in the transentorhinal cortex. As the knockouts aged, metabolic activity in the TEC waned, while it remained steady in wild-type mice. [Courtesy of Simoes et al., Cell Reports, 2021.]

Did this affect behavior? As the VPS26b knockouts aged, they had more trouble identifying novel objects in a familiar environment, or familiar objects in a new environment, than aged wild-types. When the scientists injected a viral vector carrying VPS26b into the cortices of 4-month-old knockouts to restore the protein’s expression, GluA1 levels and LTP activity normalized and memory remained intact at 7 months old.

“This is an impressive amount of work uncovering novel insights into [how] the recycling of receptors is important for learning and memory,” Gunnar Gouras, Lund University, Sweden, wrote to Alzforum (full comment below).

In AD, tau accumulates in the TEC during very early stages before spreading to the hippocampus and other cortical regions (Feb 2020 conference news; Nov 2018 conference news). In heterozygous VPS26 knockout mice, Small had previously measured higher levels of Aβ40 and Aβ42 (May 2008 news), and the neuronal VPS26b subunit seemed to mediate this. The VPS26b knockouts, but not the VPS26a heterozygotes, contained more Aβ40 and Aβ42 in their entorhinal cortices, and accumulated total tau in the cerebrospinal fluid, all with nary a human transgene to drive these changes.

What triggered this? It turns out that the knockouts were also deficient in sortilin-related receptor A. SorLA binds the retromer complex and mediates GluA1 and amyloid precursor protein (APP) trafficking. In cultured neurons, the researchers found that retromer-dependent SorLA recycling relied on VPS26b, not VPS26a. This agrees with previous research suggesting that the VPS26b retromer complex transports SorLA (Kim et al., 2010). SORL1, which encodes SorLA, is a major AD risk gene

VPS26 in People
To find out how VPS26b might affect the human TEC, the scientists first created cortical thickness maps from structural MRI scans of 188 people with AD and from 169 controls in the ADNI cohort. While they saw widespread cortical thinning in the AD brains, it was particularly notable in the TEC (see image below).

A Thinning TEC. In people with AD, MRI scans showed the most cortical thinning in the transentorhinal cortex (yellow/orange), which sits next to the amygdala (blue, left). [Courtesy of Simoes et al., Cell Reports, 2021.]

The researchers also obtained postmortem entorhinal cortex samples from eight people who had had AD and from 16 healthy controls in the Columbia University Alzheimer’s Disease Research Center brain bank. TECs from controls contained more VPS26b than did other regions of the entorhinal cortex, such as the medial, intermediate, and lateral EC, whereas expression of the other three core retromer proteins was the same across all regions. However, AD TECs had fewer retromer proteins and less SorLA than did control TECs, with the most significant deficit being in VPS26b.

“[Taken together], these findings help explain the vulnerability of the TEC in AD and emphasize dysfunctional endosomal trafficking as a unified pathogenic pathway in AD,” Charlotte Sørensen, Aarhus University, Denmark, wrote to Alzforum.

Researchers led by Young saw similar results when they deleted SORL1 from human iPSC-derived neurons (see comment below). In a preprint posted to bioRXiv, they reported impaired endosomal trafficking of GluA1 after SORL1 deletion and enhanced trafficking after its upregulation (Mishra et al., 2022). “Just like we showed for VPS26b, Young and colleagues clearly show that SorLA regulates key endosomal recycling cargo in neurons,” Small said.

Retromer Influences Neuron-Microglia Crosstalk
Does retromer dysfunction affect the brain beyond the TEC? Yasir Qureshi, first author of the second paper, looked in the hippocampus. He deleted mouse VPS35, not VPS26b, and only in hippocampal neurons. Hippocampal tissue from three-month-old knockouts expressed less GluA1, accumulated more C-terminal fragments (CTFs) of APP, and had more Iba1-positive microglia and more GFAP-positive astrocytes.

Microglial morphology was noticeably different, as well, with cells from VPS35 knockouts having shorter processes with fewer branches. They resembled dystrophic, senescent cells seen in areas of high tau burden within AD brains (Streit et al., 2009; Sep 2018 news). Injecting a viral vector carrying VPS35 into one side of the hippocampi of 3-month-old VPS35 KO mice restored APP CTFs and GluA1 to near-wild-type levels three months later. In cultured neurons, VPS35 from the viral vector bound neuronal VPS26 and VPS29 to restore retromer complex formation.

To see what was happening within neurons in vivo, the researchers homed in on SorLA. Though neurons from VPS35 knockout mice had a normal amount of SorLA, their SorLA puncta were larger, and shrunk upon reintroducing VPS35. The authors think that loss of VPS35 hindered the retromer’s ability to shuttle SorLA along, creating engorged endosomes (Jun 2020 news).

The scientists next turned their attention to glia. Replenishing VPS35 reduced astrocyte, but not microglial, activation. However, both the number of microglial branches, and their lengths, grew back to levels seen in controls (see image below).

VPS35 Restores Microglia. Compared to microglia isolated from wild-type mice (left), those from VPS35 knockouts had short, stubby branches (middle). Replenishing VPS35 in neurons normalized the phenotype (right). [Courtesy of Qureshi et al., Cell Reports, 2022.]

Peng Jiang, Rutgers University, New Jersey, was surprised that microglia in the VPS35 knockout mice looked like the dystrophic microglia seen in AD. "This is very exciting because mouse models typically do not fully recapitulate microglial pathology seen in AD," he wrote to Alzforum. Qureshi is collecting single-nuclei and spatial transcriptomic data to see if the microglia are similar to disease-associated microglia found in AD and other neurodegenerative diseases (Jun 2017 news; Sep 2017 news).

How did restoring the retromer in neurons change glia? Previously, Simoes had detected high levels of tau within the CSF of the VPS35 knockout mice (Dec 2020 news). However, tau does not seem to be involved here. Double VPS35/tau knockouts displayed neuronal and glial phenotypes similar to the VPS35 KOs, suggesting to the authors that downstream effects of retromer dysfunction are independent of tau. The molecule(s) facilitating this neuron-microglia crosstalk remain at large.—Chelsea Weidman Burke

Comments

  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., 2010Kim 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:

    . 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.

    . 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.

    . Apolipoprotein E4 genotype compromises brain exosome production. Brain. 2019 Jan 1;142(1):163-175. PubMed.

    . 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.

    . 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.

    . 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.

    . 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.

    . 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.

  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:

    . Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol. 2014 Jun;10(6):443-9. Epub 2014 Apr 20 PubMed.

    . 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.

    . The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons. bioRxiv. January 11, 2022 BioRxiv.

  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:

    . 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.

    . The Retromer Supports AMPA Receptor Trafficking During LTP. Neuron. 2017 Apr 5;94(1):74-82.e5. PubMed.

    . 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.

  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).

  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.

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References

News Citations

  1. Can PET Match Up Areas of Protein Deposit With Alzheimer’s Symptoms?
  2. It’s Official: Tau PET Sees Tangles, and Staging Tangles Predicts Decline
  3. Mice, Flies Further Implicate Retromer in AD Pathogenesis
  4. Are Tauopathies Caused by Neuronal and Glial Senescence?
  5. Without SORL1, Endosomes Swell in Neurons but not Microglia
  6. Hot DAM: Specific Microglia Engulf Plaques
  7. ApoE and Trem2 Flip a Microglial Switch in Neurodegenerative Disease
  8. Biomarkers of Errant Endosome Spotted in Cerebrospinal Fluid

Alzpedia Citations

  1. SORLA (SORL1)

Paper Citations

  1. . Structure of the membrane-assembled retromer coat determined by cryo-electron tomography. Nature. 2018 Sep;561(7724):561-564. Epub 2018 Sep 17 PubMed.
  2. . Vps26A and Vps26B subunits define distinct retromer complexes. Traffic. 2011 Dec;12(12):1759-73. Epub 2011 Oct 17 PubMed.
  3. . Retromer mediates a discrete route of local membrane delivery to dendrites. Neuron. 2014 Apr 2;82(1):55-62. PubMed.
  4. . The Retromer Supports AMPA Receptor Trafficking During LTP. Neuron. 2017 Apr 5;94(1):74-82.e5. PubMed.
  5. . Implication of mouse Vps26b-Vps29-Vps35 retromer complex in sortilin trafficking. Biochem Biophys Res Commun. 2010 Dec 10;403(2):167-71. Epub 2010 Oct 30 PubMed.
  6. . The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons. bioRxiv. January 11, 2022 BioRxiv.
  7. . Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol. 2009 Oct;118(4):475-85. PubMed.

External Citations

  1. risk gene

Further Reading

Papers

  1. . In vivo evidence that SORL1, encoding the endosomal recycling receptor SORLA, can function as a causal gene in Alzheimer’s Disease. bioRxiv. July 13, 2021

Primary Papers

  1. . Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling. Cell Rep. 2021 Dec 28;37(13):110182. PubMed.
  2. . The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease. Cell Rep. 2022 Jan 18;38(3):110262. PubMed.