The aggregation of the peptide hormone amylin in the pancreas is a pathological hallmark of type-2 diabetes. Additionally, amylin can form aggregates in the brain, promoting β-amyloid deposition and tau phosphorylati...The aggregation of the peptide hormone amylin in the pancreas is a pathological hallmark of type-2 diabetes. Additionally, amylin can form aggregates in the brain, promoting β-amyloid deposition and tau phosphorylation in Alzheimer's disease. The cross-seeding between amylin and tau exacerbates tau pathology spread and synaptic loss, leading to neurodegeneration and cognitive deficits. Given the link between lysosomal dysfunction and tauopathy in the brain and amylin aggregation in the pancreas, we hypothesized that amylin could potentially worsen tau pathology in diabetic mice. We administered streptozotocin and/or amylin peripherally to the PS19 model of tauopathy at 3 months and characterized them at 6 months of age. We found that streptozotocin diminished body weight gain, increased blood glucose levels, worsened motor performance, and improved fear-conditioned memory in PS19 mice. Both amylin and streptozotocin administration prompted the emergence of tau pathology in the pancreas, which coincided with a decrease in the number of lysosomes in pancreatic islets. Mice treated with amylin and streptozotocin also developed robust tau pathology concomitant with lowering lysosomal cathepsin D levels in the visual cortex. These findings suggest that in diabetic mice, amylin administration diminished pancreatic lysosomes, possibly increasing the number of amylin aggregates that reached the brain and contributing to the worsening of tau pathology due to lysosomal impairment in the visual cortex. The outcome of our research enhances the understanding of the cellular pathways by which amylin may serve as a link between the pancreas-brain axis during diabetes, influencing the risk of developing tau pathology.展开更多
Lipofuscin,a marker of aging,is the accumulation of autofluorescent granules within microglia and postmitotic cells such as neurons.Lipofuscin has traditionally been regarded as an inert byproduct of cellular degradat...Lipofuscin,a marker of aging,is the accumulation of autofluorescent granules within microglia and postmitotic cells such as neurons.Lipofuscin has traditionally been regarded as an inert byproduct of cellular degradation.However,recent findings suggest that lipofuscin may play a role in modulating age-related neurodegenerative processes,and several questions remain unanswered.For instance,why do lipofuscin granules accumulate preferentially in aged neurons and microglia?What happens to these pigments upon neuronal demise?Particularly in neurodegenerative diseases like Alzheimer’s disease(AD),why does amyloidβ(Aβ)deposition usually begin in late adulthood or during aging?Why do lipofuscin and amyloid plaques appear preferentially in grey matter and rarely in white matter?In this review,we argue that lipofuscin should be revisited not as a simple biomarker of aging,but as a potential modulator of neurodegenerative diseases.We synthesize emerging evidence linking lipofuscin to lysosomal dysfunction,oxidative stress,lipid peroxidation and disease onset—mechanisms critically implicated in neurodegeneration.We also explore the potential interactions of lipofuscin with Aβand their spatial location,and summarize evidence showing that lipofuscin may influence disease progression via feedback loops affecting cellular clearance and inflammation.Finally,we propose future research directions toward better understanding of the mechanisms of lipofuscin accumulation and improved lysosomal waste clearance in aging.展开更多
Background The accumulation ofα-synuclein(α-syn),an essential step in PD development and progression,is observed not only in neurons but also in glia,including astrocytes.The mechanisms regulating astrocyticα-syn l...Background The accumulation ofα-synuclein(α-syn),an essential step in PD development and progression,is observed not only in neurons but also in glia,including astrocytes.The mechanisms regulating astrocyticα-syn level and aggregation remain unclear.More recently,it has been demonstrated that a part ofα-syn spreading occurs through extracellular vesicles(EVs),although it is unknown whether this process is involved in astrocytes of PD.It is known,however,that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders.Methods Primary astrocytes were transfected with A53Tα-syn plasmid or exposed toα-syn aggregates.The level of astrocyte-derived EVs(AEVs)was assessed by nanoparticle tracking analysis and immunofluorescence.The lysosomal function was evaluated by Cathepsin assays,immunofluorescence for levels of Lamp1 and Lamp2,and LysoTracker Red staining.The Apogee assays were optimized to measure the GLT-1+AEVs in clinical cohorts of 106 PD,47 multiple system atrophy(MSA),and 103 healthy control(HC)to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism.Results The number of AEVs significantly increased in primary astrocytes withα-syn deposition.The mechanism of increased AEVs was partially attributed to lysosomal dysfunction.The number ofα-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA.The integrative model combining AEVs with total and aggregatedα-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915,and from MSA with an AUC of 0.877.Conclusions Pathologicalα-syn deposition could increase the astrocytic secretion of EVs,possibly throughα-syninduced lysosomal dysfunction.Theα-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.展开更多
基金supported by the US National Institutes on Aging grant AG057290.
文摘The aggregation of the peptide hormone amylin in the pancreas is a pathological hallmark of type-2 diabetes. Additionally, amylin can form aggregates in the brain, promoting β-amyloid deposition and tau phosphorylation in Alzheimer's disease. The cross-seeding between amylin and tau exacerbates tau pathology spread and synaptic loss, leading to neurodegeneration and cognitive deficits. Given the link between lysosomal dysfunction and tauopathy in the brain and amylin aggregation in the pancreas, we hypothesized that amylin could potentially worsen tau pathology in diabetic mice. We administered streptozotocin and/or amylin peripherally to the PS19 model of tauopathy at 3 months and characterized them at 6 months of age. We found that streptozotocin diminished body weight gain, increased blood glucose levels, worsened motor performance, and improved fear-conditioned memory in PS19 mice. Both amylin and streptozotocin administration prompted the emergence of tau pathology in the pancreas, which coincided with a decrease in the number of lysosomes in pancreatic islets. Mice treated with amylin and streptozotocin also developed robust tau pathology concomitant with lowering lysosomal cathepsin D levels in the visual cortex. These findings suggest that in diabetic mice, amylin administration diminished pancreatic lysosomes, possibly increasing the number of amylin aggregates that reached the brain and contributing to the worsening of tau pathology due to lysosomal impairment in the visual cortex. The outcome of our research enhances the understanding of the cellular pathways by which amylin may serve as a link between the pancreas-brain axis during diabetes, influencing the risk of developing tau pathology.
基金supported by the JSPS KAKENHI Grant-in-Aid for Start-Up Research Activity Grant Number 22K20681(G.D.)JSPS KAKENHI Grant-in-Aid for Early-Career Scientist Grant Number 23K14672(G.D.)+5 种基金Niigata University Brain Research Institute Brodmann Project Research Grant Number 543103(G.D.)Niigata University School of Medicine Tsukada Medical Scholarship Grant Number J11F0701(G.D.)the Takeda Science Foundation(H.M.)JSPS KAKENHI Grant Number JP 22484842(H.M.),JP 23790744(H.M.)AMED Grant Number JP23gm1710010(H.M.),JP24wm0625506(H.M.)JST Moonshot R&D Grant Number JPMJMS2024](H.M.).
文摘Lipofuscin,a marker of aging,is the accumulation of autofluorescent granules within microglia and postmitotic cells such as neurons.Lipofuscin has traditionally been regarded as an inert byproduct of cellular degradation.However,recent findings suggest that lipofuscin may play a role in modulating age-related neurodegenerative processes,and several questions remain unanswered.For instance,why do lipofuscin granules accumulate preferentially in aged neurons and microglia?What happens to these pigments upon neuronal demise?Particularly in neurodegenerative diseases like Alzheimer’s disease(AD),why does amyloidβ(Aβ)deposition usually begin in late adulthood or during aging?Why do lipofuscin and amyloid plaques appear preferentially in grey matter and rarely in white matter?In this review,we argue that lipofuscin should be revisited not as a simple biomarker of aging,but as a potential modulator of neurodegenerative diseases.We synthesize emerging evidence linking lipofuscin to lysosomal dysfunction,oxidative stress,lipid peroxidation and disease onset—mechanisms critically implicated in neurodegeneration.We also explore the potential interactions of lipofuscin with Aβand their spatial location,and summarize evidence showing that lipofuscin may influence disease progression via feedback loops affecting cellular clearance and inflammation.Finally,we propose future research directions toward better understanding of the mechanisms of lipofuscin accumulation and improved lysosomal waste clearance in aging.
基金supported by the National Natural Science Foundation of China(82020108012,82001200,81571226 and 81671187)the Natural Science Foundation of Zhejiang Province(LZ23H090002)+1 种基金the Leading Innovation and Entrepreneurship Team in Zhejiang Province(2020R01001)Innovative Institute of Basic Medical Science of Zhejiang University.
文摘Background The accumulation ofα-synuclein(α-syn),an essential step in PD development and progression,is observed not only in neurons but also in glia,including astrocytes.The mechanisms regulating astrocyticα-syn level and aggregation remain unclear.More recently,it has been demonstrated that a part ofα-syn spreading occurs through extracellular vesicles(EVs),although it is unknown whether this process is involved in astrocytes of PD.It is known,however,that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders.Methods Primary astrocytes were transfected with A53Tα-syn plasmid or exposed toα-syn aggregates.The level of astrocyte-derived EVs(AEVs)was assessed by nanoparticle tracking analysis and immunofluorescence.The lysosomal function was evaluated by Cathepsin assays,immunofluorescence for levels of Lamp1 and Lamp2,and LysoTracker Red staining.The Apogee assays were optimized to measure the GLT-1+AEVs in clinical cohorts of 106 PD,47 multiple system atrophy(MSA),and 103 healthy control(HC)to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism.Results The number of AEVs significantly increased in primary astrocytes withα-syn deposition.The mechanism of increased AEVs was partially attributed to lysosomal dysfunction.The number ofα-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA.The integrative model combining AEVs with total and aggregatedα-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915,and from MSA with an AUC of 0.877.Conclusions Pathologicalα-syn deposition could increase the astrocytic secretion of EVs,possibly throughα-syninduced lysosomal dysfunction.Theα-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.
