Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models

Minami, S. Sakura; Min, Sang‐Won; Krabbe, Grietje; Wang, Chao; Zhou, Yungui; Asgarov, Rustam; Li, Yaqiao; Martens, Lauren Herl; Elia, Lisa P.; Ward, Michael E.; Mucke, Lennart; Farese, Robert V.; Gan, Li

doi:10.1038/nm.3672

Cited by 205 publications

(211 citation statements)

References 62 publications

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“…Interestingly, it was recently reported (based on genetic perturbations) that microglial PGRN limits amyloid plaque deposition in a mouse AD model (31). However, although microglia can phagocytose and digest aggregated Aβ in a lysosome-dependent manner (22,62,63), our data indicate that they contributed only a small part to the steady-state pool of PGRN and lysosomes around amyloid plaques.…”

Section: Discussioncontrasting

confidence: 43%

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

314

326

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Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.

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Section: Discussioncontrasting

confidence: 43%

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

314

326

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“…Additionally, progranulin localizes at the margins of amyloid plaques in both mouse and human postmortem brain tissue, and increased progranulin mRNA levels have been reported in the brains of multiple AD‐mouse models 13. Overexpression of progranulin in these models has been shown to slow plaque deposition and cognitive decline 14, 15. Taken together, these data suggest a direct role of progranulin in AD pathogenesis.…”

Section: Introductionmentioning

confidence: 81%

“…Previous studies in mouse models of AD have found that the artificial increase in progranulin levels can slow disease progression including disrupting A β plaque deposition and neurotoxicity 14. Furthermore, loss‐of‐function mutations in the progranulin gene are risk factors for developing AD as well as other neurodegenerative disorders 4, 6, 8.…”

Section: Discussionmentioning

confidence: 99%

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

Cooper

Nachun

Dokuru

et al. 2018

Ann Clin Transl Neurol

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ObjectiveChanges in progranulin (GRN) expression have been hypothesized to alter risk for Alzheimer's disease (AD). We investigated the relationship between GRN expression in peripheral blood and clinical diagnosis of AD and mild cognitive impairment (MCI).MethodsPeripheral blood progranulin gene expression was measured, using microarrays from Alzheimer's (n = 186), MCI (n = 118), and control (n = 204) subjects from the University of California San Francisco Memory and Aging Center (UCSF‐MAC) and two independent published series (AddNeuroMed and ADNI). GRN gene expression was correlated with clinical, demographic, and genetic data, including APOE haplotype and the GRN rs5848 single‐nucleotide polymorphism. Finally, we assessed progranulin protein levels, using enzyme‐linked immunosorbent assay, and methylation status using methylation microarrays.ResultsWe observed an increase in blood progranulin gene expression and a decrease in GRN promoter methylation in males (P = 0.007). Progranulin expression was 13% higher in AD and MCI patients compared with controls in the UCSF‐MAC cohort (F 2,505 = 10.41, P = 3.72*10−5). This finding was replicated in the AddNeuroMed (F 2,271 = 17.9, P = 4.83*10−8) but not the ADNI series. The rs5848 SNP (T‐allele) predicted decreased blood progranulin gene expression (P = 0.03). The APOE4 haplotype was positively associated with progranulin expression independent of diagnosis (P = 0.04). Finally, we did not identify differences in plasma progranulin protein levels or gene methylation between diagnostic categories.InterpretationProgranulin mRNA is elevated in peripheral blood of patients with AD and MCI and its expression is associated with numerous genetic and demographic factors. These data suggest a role in the pathogenesis of neurodegenerative dementias besides frontotemporal dementia.

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“…Similarly, haploinsufficiency in another microglial-expressed gene, PGRN, is a common genetic cause of FTD, and also confers elevated risk of developing AD (53). PGRN acts as an inflammatory modulator and facilitates microglial phagocytosis of amyloid-β (Aβ) and apoptotic cells (54,55). Lack of PGRN leads to dysregulation of microglial complement gene expression and loss of synaptic pruning and lysosome maturation (56).…”

Section: Microglia In Als: Lessons From Sod1mentioning

confidence: 99%

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Lall¹,

Baloh²

2017

Journal of Clinical Investigation

140

102

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Genetic connections between microglia and neurodegenerationMicroglia are the main cells in the CNS responsible for immune surveillance and are critical for normal development and homeostasis (34)(35)(36). Under steady-state conditions, "ramified" microglia continuously survey the local microenvironment for any foreign antigens and insults. The resident microglia are Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease. This Review highlights the contribution of microglia to ALS/FTD pathogenesis, discusses the connection between autoimmunity and ALS/FTD, and explores the possibility that C9orf72 and other ALS/FTD genes may have a "dual effect" on both neuronal and myeloid cell function that could explain a shared propensity for altered systemic immunity and neurodegeneration.

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Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models

Cited by 205 publications

References 62 publications

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

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