Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2022

Open Access 01-12-2022 | Alzheimer's Disease | Research

Microglial VPS35 deficiency impairs Aβ phagocytosis and Aβ-induced disease-associated microglia, and enhances Aβ associated pathology

Authors: Xiao Ren, Lingling Yao, YongGang Wang, Lin Mei, Wen-Cheng Xiong

Published in: Journal of Neuroinflammation | Issue 1/2022

Login to get access

Abstract

Background

Vacuolar sorting protein 35 (VPS35), a key component of the retromer, plays an essential role in selectively retrieval of transmembrane proteins from endosomes to trans-Golgi networks. Dysfunctional retromer is a risk factor for neurodegenerative disorders, including Alzheimer’s disease (AD). Microglial VPS35 deficiency is found in AD patients’ brain; however, it remains unclear if and how microglial VPS35-loss contributes to AD development.

Methods

We used mice with VPS35 cKO (conditional knockout) in microglial cells in 5XFAD, an AD mouse model. The AD related brain pathology (Aβ and glial activation), behavior, and phagocytosis of Aβ were accessed by a combination of immunofluorescence staining analyses and neurological behavior tests.

Results

A decrease in learning and memory function, but increases in insoluble, fibrillar, and plaques of β-amyloids (Aβ), dystrophic neurites, and reactive astrocytes are observed in microglial VPS35 deficient 5XFAD mice. Further examining microglial phenotype demonstrates necessity of microglial VPS35 in disease-associated microglia (DAM) development and microglial uptake of Aβ, revealing a tight association of microglial Aβ uptake with DAM development.

Conclusions

Together, these results uncovered a mechanism by which microglial VPS35-deficiency precipitates AD pathology in 5XFAD mice likely by impairing DAM development and DAM mediated Aβ uptake and clearance, and thus accelerating the cognition decline.
Appendix
Available only for authorised users
Literature
1.
Minati L, Edginton T, Grazia Bruzzone M, Giaccone G. Reviews: current concepts in Alzheimer’s disease: a multidisciplinary review. Am J Alzheimer’s Dis Other Dementias. 2009;24:95–121.CrossRef
2.
Carr D, Goate A, Phil D, Morris J. Current concepts in the pathogenesis of Alzheimer’s disease. Am J Med. 1997;103:3S-10S.PubMedCrossRef
3.
Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harbor Perspect Med. 2011;1:a006189.CrossRef
4.
Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, Van Der Lee SJ, Amlie-Wolf A. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019;51:414–30.PubMedPubMedCentralCrossRef
5.
Lee CD, Landreth GE. The role of microglia in amyloid clearance from the AD brain. J Neural Transm. 2010;117:949–60.PubMedCrossRef
6.
Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17:157–72.PubMedCrossRef
7.
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 2017;169:1276–90.PubMedCrossRef
8.
Tang FL, Liu W, Hu JX, Erion JR, Ye J, Mei L, Xiong WC. VPS35 deficiency or mutation causes dopaminergic neuronal loss by impairing mitochondrial fusion and function. Cell Rep. 2015;12:1631–43.PubMedPubMedCentralCrossRef
9.
Wen L, Tang F-L, Hong Y, Luo S-W, Wang C-L, He W, Shen C, Jung J-U, Xiong F, Lee D-h. VPS35 haploinsufficiency increases Alzheimer’s disease neuropathology. J Cell Biol. 2011;195:765–79.PubMedPubMedCentralCrossRef
10.
Tang F-L, Erion JR, Tian Y, Liu W, Yin D-M, Ye J, Tang B, Mei L, Xiong W-C. VPS35 in dopamine neurons is required for endosome-to-Golgi retrieval of Lamp2a, a receptor of chaperone-mediated autophagy that is critical for α-synuclein degradation and prevention of pathogenesis of Parkinson’s disease. J Neurosci. 2015;35:10613–28.PubMedPubMedCentralCrossRef
11.
Muhammad A, Flores I, Zhang H, Yu R, Staniszewski A, Planel E, Herman M, Ho L, Kreber R, Honig LS. Retromer deficiency observed in Alzheimer’s disease causes hippocampal dysfunction, neurodegeneration, and Aβ accumulation. Proc Natl Acad Sci. 2008;105:7327–32.PubMedPubMedCentralCrossRef
12.
Small SA, Petsko GA. Retromer in Alzheimer disease, Parkinson disease and other neurological disorders. Nat Rev Neurosci. 2015;16:126–32.PubMedCrossRef
13.
Zhang H, Huang T, Hong Y, Yang W, Zhang X, Luo H, Xu H, Wang X. The retromer complex and sorting nexins in neurodegenerative diseases. Front Aging Neurosci. 2018;10:79.PubMedPubMedCentralCrossRef
14.
Small SA, Kent K, Pierce A, Leung C, Kang MS, Okada H, Honig L, Vonsattel JP, Kim TW. Model-guided microarray implicates the retromer complex in Alzheimer’s disease. Ann Neurol. 2005;58:909–19.PubMedCrossRef
15.
Appel JR, Ye S, Tang F, Sun D, Zhang H, Mei L, Xiong WC. Increased microglial activity, impaired adult hippocampal neurogenesis, and depressive-like behavior in microglial VPS35-depleted mice. J Neurosci. 2018;38:5949–68.PubMedPubMedCentralCrossRef
16.
Yin J, Liu X, He Q, Zhou L, Yuan Z, Zhao S. Vps35-dependent recycling of Trem2 regulates microglial function. Traffic. 2016;17:1286–96.PubMedCrossRef
17.
Tang FL, Zhao L, Zhao Y, Sun D, Zhu XJ, Mei L, Xiong WC. Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons. Cell Death Differ. 2020;27:2099–116.PubMedPubMedCentralCrossRef
18.
Zhao Y, Tang F, Lee D, Xiong WC. Expression of low level of VPS35-mCherry fusion protein diminishes Vps35 depletion induced neuron terminal differentiation deficits and neurodegenerative pathology, and prevents neonatal death. Int J Mol Sci. 2021;22:8394.PubMedPubMedCentralCrossRef
19.
Ye SY, Apple JE, Ren X, Tang FL, Yao LL, Wang YG, Mei L, Zhou YG, Xiong WC. Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex. J Neuroinflammation. 2019;16:235.PubMedPubMedCentralCrossRef
20.
Lucin KM, O’Brien CE, Bieri G, Czirr E, Mosher KI, Abbey RJ, Mastroeni DF, Rogers J, Spencer B, Masliah E. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease. Neuron. 2013;79:873–86.PubMedPubMedCentralCrossRef
21.
Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26:10129–40.PubMedPubMedCentralCrossRef
22.
Meilandt WJ, Ngu H, Gogineni A, Lalehzadeh G, Lee SH, Srinivasan K, Imperio J, Wu T, Weber M, Kruse AJ, et al. Trem2 deletion reduces late-stage amyloid plaque accumulation, elevates the Abeta42:Abeta40 ratio, and exacerbates axonal dystrophy and dendritic spine loss in the PS2APP Alzheimer’s mouse model. J Neurosci. 2020;40:1956–74.PubMedPubMedCentralCrossRef
23.
Drummond E, Nayak S, Faustin A, Pires G, Hickman RA, Askenazi M, Cohen M, Haldiman T, Kim C, Han X, et al. Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease. Acta Neuropathol. 2017;133:933–54.PubMedPubMedCentralCrossRef
24.
Zhang H, Chen W, Tan Z, Zhang L, Dong Z, Cui W, Zhao K, Wang H, Jing H, Cao R, et al. A role of low-density lipoprotein receptor-related protein 4 (LRP4) in astrocytic abeta clearance. J Neurosci. 2020;40:5347–61.PubMedPubMedCentralCrossRef
25.
Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E, Raja WK, Cheng J, et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron. 2018;98:1294.PubMedPubMedCentralCrossRef
26.
Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, Roth K, Aguzzi A, Staufenbiel M, Walker LC, Jucker M. Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci U S A. 2009;106:12926–31.PubMedPubMedCentralCrossRef
27.
Faucher P, Mons N, Micheau J, Louis C, Beracochea DJ. Hippocampal injections of oligomeric amyloid beta-peptide (1–42) induce selective working memory deficits and long-lasting alterations of ERK signaling pathway. Front Aging Neurosci. 2015;7:245.PubMed
28.
Ren X, Yao LL, Pan JX, Zhang JS, Mei L, Wang YG, Xiong WC. Linking cortical astrocytic neogenin deficiency to the development of Moyamoya disease-like vasculopathy. Neurobiol Dis. 2021;154:105339.PubMedCrossRef
29.
Sun D, Sun XD, Zhao L, Lee DH, Hu JX, Tang FL, Pan JX, Mei L, Zhu XJ, Xiong WC. Neogenin, a regulator of adult hippocampal neurogenesis, prevents depressive-like behavior. Cell Death Dis. 2018;9:8.PubMedPubMedCentralCrossRef
30.
Kraeuter AK, Guest PC, Sarnyai Z. The Y-maze for assessment of spatial working and reference memory in mice. Methods Mol Biol. 2019;1916:105–11.PubMedCrossRef
31.
Jawhar S, Trawicka A, Jenneckens C, Bayer TA, Wirths O. Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Abeta aggregation in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol Aging. 2012;33(196):e129-140.
32.
Benzing WC, Mufson EJ, Armstrong DM. Alzheimer’s disease-like dystrophic neurites characteristically associated with senile plaques are not found within other neurodegenerative diseases unless amyloid beta-protein deposition is present. Brain Res. 1993;606:10–8.PubMedCrossRef
33.
Sharoar MG, Hu X, Ma X-M, Zhu X, Yan R. Sequential formation of different layers of dystrophic neurites in Alzheimer’s brains. Mol Psychiatry. 2019;24:1369–82.PubMedPubMedCentralCrossRef
34.
Sharoar MG, Palko S, Ge Y, Saido TC, Yan R. Accumulation of saposin in dystrophic neurites is linked to impaired lysosomal functions in Alzheimer’s disease brains. Mol Neurodegener. 2021;16:45.PubMedPubMedCentralCrossRef
35.
Shi Q, Hu X, Prior M, Yan R. The occurrence of aging-dependent reticulon 3 immunoreactive dystrophic neurites decreases cognitive function. J Neurosci. 2009;29:5108–15.PubMedPubMedCentralCrossRef
36.
Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology. 2004;62:925–31.PubMedCrossRef
37.
Raber J, Huang Y, Ashford JW. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging. 2004;25:641–50.PubMedCrossRef
38.
39.
Scarmeas N, Brandt J, Blacker D, Albert M, Hadjigeorgiou G, Dubois B, Devanand D, Honig L, Stern Y. Disruptive behavior as a predictor in Alzheimer disease. Arch Neurol. 2007;64:1755–61.PubMedPubMedCentralCrossRef
40.
Forner S, Kawauchi S, Balderrama-Gutierrez G, Kramar EA, Matheos DP, Phan J, Javonillo DI, Tran KM, Hingco E, da Cunha C, et al. Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer’s disease. Sci Data. 2021;8:270.PubMedPubMedCentralCrossRef
41.
Kimura R, Ohno M. Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiol Dis. 2009;33:229–35.PubMedCrossRef
42.
Zhang H, Kang E, Wang Y, Yang C, Yu H, Wang Q, Chen Z, Zhang C, Christian KM, Song H, et al. Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice. Nat Commun. 2016; 7.
43.
44.
Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman BT. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature. 2008;451:720–4.PubMedPubMedCentralCrossRef
45.
Rangaraju S, Dammer EB, Raza SA, Rathakrishnan P, Xiao H, Gao T, Duong DM, Pennington MW, Lah JJ, Seyfried NT, Levey AI. Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease. Mol Neurodegener. 2018;13:24.PubMedPubMedCentralCrossRef
46.
47.
Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, Mulinyawe SB, Bohlen CJ, Adil A, Tucker A, et al. New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci U S A. 2016;113:E1738-1746.PubMedPubMedCentralCrossRef
48.
49.
Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O’Loughlin E, Xu Y, Fanek Z, et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 2017;47:566–81.PubMedPubMedCentralCrossRef
50.
Grubman A, Choo XY, Chew G, Ouyang JF, Sun G, Croft NP, Rossello FJ, Simmons R, Buckberry S, Landin DV, et al. Transcriptional signature in microglia associated with Abeta plaque phagocytosis. Nat Commun. 2021;12:3015.PubMedPubMedCentralCrossRef
51.
Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I. Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell. 2018;173:1073–81.PubMedCrossRef
52.
Hampel H, Hardy J, Blennow K, Chen C, Perry G, Kim SH, Villemagne VL, Aisen P, Vendruscolo M, Iwatsubo T, et al. The amyloid-beta pathway in Alzheimer’s disease. Mol Psychiatry. 2021;26:5481.PubMedPubMedCentralCrossRef
53.
54.
Spiller KJ, Restrepo CR, Khan T, Dominique MA, Fang TC, Canter RG, Roberts CJ, Miller KR, Ransohoff RM, Trojanowski JQ, Lee VM. Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy. Nat Neurosci. 2018;21:329–40.PubMedPubMedCentralCrossRef
55.
Wolfe CM, Fitz NF, Nam KN, Lefterov I, Koldamova R. The role of APOE and TREM2 in Alzheimer’s disease-current understanding and perspectives. Int J Mol Sci. 2018;20:81.PubMedCentralCrossRef
56.
Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M, Ghasemigharagoz A, Katzmarski N, et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci. 2019;22:191–204.PubMedPubMedCentralCrossRef
57.
Fitz NF, Nam KN, Wolfe CM, Letronne F, Playso BE, Iordanova BE, Kozai TDY, Biedrzycki RJ, Kagan VE, Tyurina YY, et al. Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease. Nat Commun. 2021;12:3416.PubMedPubMedCentralCrossRef
Metadata
Title
Microglial VPS35 deficiency impairs Aβ phagocytosis and Aβ-induced disease-associated microglia, and enhances Aβ associated pathology
Authors
Xiao Ren
Lingling Yao
YongGang Wang
Lin Mei
Wen-Cheng Xiong
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-022-02422-0

Other articles of this Issue 1/2022

Journal of Neuroinflammation 1/2022 Go to the issue

Research

Macrophage-based delivery of interleukin-13 improves functional and histopathological outcomes following spinal cord injury

Research

Lactate attenuates astrocytic inflammation by inhibiting ubiquitination and degradation of NDRG2 under oxygen–glucose deprivation conditions

Research

Motoneuronal inflammasome activation triggers excessive neuroinflammation and impedes regeneration after sciatic nerve injury

Research

Chronic allergic lung inflammation negatively influences neurobehavioral outcomes in mice

Research

Comparative analysis of transcriptome remodeling in plaque-associated and plaque-distant microglia during amyloid-β pathology progression in mice

Research

A novel aquaporin-4-associated optic neuritis rat model with severe pathological and functional manifestations