Tau Seeds in Extracellular Vesicles Induce Tau Accumulation in Degradative Organelles of Cells

Pedrioli, Giona; Barberis, Marialuisa; Magrin, Claudia; Morone, Diego; Piovesana, Ester; Senesi, Giorgia; Sola, Martina; Papin, Stéphanie; Paganetti, Paolo

doi:10.1089/dna.2021.0485

“…Based on our data, we propose that lysosomal dysfunction and the presence of internalized Tau seeds may cause, through an unknown mechanism, the accumulation of Tau on route to degradation within DOs. Similar results were described in murine cells incubated with exosomes containing a brillogenic fragment of Tau 23 . Tau accumulation in DOs was associated to increased lactosylceramide and lysosomal stress, indicating that seeded accumulation of Tau and impairment of lysosomal function and lipid metabolism are reciprocally engaged in a sequence of harmful events.…”

Section: Discussionsupporting

confidence: 86%

“…We reported that brillogenic fragments of Tau carried by extracellular vesicles induced an aberrant accumulation of intracellular Tau within DOs of neuroblastoma cells 23 . So, next we studied whether Tau accumulation may occur also in DOs of human primary broblasts incubated with brillogenic seeds.…”

Section: Resultsmentioning

confidence: 97%

“…Tau localizes in DOs upon autophagy stimulation Pharmacologic manipulation of the ALP system was performed to assess whether Tau may represent a substrate of autophagy 23 and be targeted to degradative organelles (DOs) of human broblasts.…”

Section: Resultsmentioning

confidence: 99%

“…The plasmid pInducer20, a gift from Stephen Elledge (Addgene plasmid # 44012), was the vector for teton inducible expression of Tau 2N4R in human primary broblasts. The cDNAs (Supplementary Table 1) were ampli ed by the polymerase chain reaction (PCR) using human full-length templates and speci c oligonucleotide primers from parental plasmids already available in the laboratory 23 . The cDNAs were rst inserted in the pENTRY4 backbone (A10561, Invitrogen) before recombination with Gateway LR Clonase II (11791-020, Invitrogen) following the instructions of the manufacturer.…”

Section: Dna Plasmidsmentioning

confidence: 99%

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Tau Accumulation in Degradative Organelles is Associated to Lysosomal Stress

Piovesana,

Magrin,

Ciccaldo

et al. 2023

Preprint

Self Cite

1

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Neurodegenerative disorders are characterized by the brain deposition of insoluble amyloidogenic proteins, such as α-synuclein or Tau, and the concomitant deterioration of cell functions such as the autophagy-lysosomal pathway (ALP). The ALP is involved in the degradation of intracellular macromolecules including protein aggregates. ALP dysfunction due to inherited defects in lysosomal or non-lysosomal proteins causes a group of diseases called lysosomal storage disorders (LSD) because of abnormal accumulation of lysosomal degradation substrates. Supporting the contribution of ALP defects in neurodegenerative diseases, deposition of amyloidogenic proteins occurs in LSD. Moreover, heterozygous mutations of several ALP genes represent risk factors for Parkinson’s disease. The reciprocal contribution of α-synuclein accumulation and lysosomal dysfunction have been extensively studied. However, whether this adverse crosstalk also embraces Tau pathology needs more investigation. Here, we show in human primary fibroblasts that Tau seeds isolated from the brain of Alzheimer’s disease induce Tau accumulation in acidic degradative organelles and lysosomal stress. Furthermore, inhibition of glucocerebrosidase, a lysosomal enzyme mutated in Gaucher’s disease and a main risk for Parkinson’s disease, causes lysosomal dysfunction in primary fibroblasts and contributes to the accumulation of Tau. Considering the presence of Tau lesions in Parkinson’s disease as well as in multiple neurodegenerative disorders including Alzheimer’s disease, our data call for further studies on strategies to alleviate ALP dysfunction as new therapeutic opportunity for neurodegenerative diseases and LSD.

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“…These findings suggest that the ApoE ε4 genotype may predispose to decreased exosome release, in turn inducing endolysosomal damage and leading to neuronal vulnerability and a higher risk of AD ( Peng et al, 2019 ). On the other hand, the EV-delivery of toxic Tau species also contributes to the malfunction of degradative organelles, further contributing to Tau accumulation ( Pedrioli et al, 2021 ).…”

Section: Evs In Alzheimer’s Disease Brain Pathologymentioning

confidence: 99%

Extracellular vesicles and Alzheimer’s disease in the novel era of Precision Medicine: implications for disease progression, diagnosis and treatment

Gomes

¹

,

Tzouanou

²

,

Skolariki

³

et al. 2022

Experimental Neurology

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Tau accumulation in degradative organelles is associated to lysosomal stress

Piovesana,

Magrin,

Ciccaldo

et al. 2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

Neurodegenerative disorders are characterized by the brain deposition of insoluble amyloidogenic proteins, such as α-synuclein or Tau, and the concomitant deterioration of cell functions such as the autophagy-lysosomal pathway (ALP). The ALP is involved in the degradation of intracellular macromolecules including protein aggregates. ALP dysfunction due to inherited defects in lysosomal or non-lysosomal proteins causes a group of diseases called lysosomal storage disorders (LSD) because of abnormal accumulation of lysosomal degradation substrates. Supporting the contribution of ALP defects in neurodegenerative diseases, deposition of amyloidogenic proteins occurs in LSD. Moreover, heterozygous mutations of several ALP genes represent risk factors for Parkinson’s disease. The reciprocal contribution of α-synuclein accumulation and lysosomal dysfunction have been extensively studied. However, whether this adverse crosstalk also embraces Tau pathology needs more investigation. Here, we show in human primary fibroblasts that Tau seeds isolated from the brain of Alzheimer’s disease induce Tau accumulation in acidic degradative organelles and lysosomal stress. Furthermore, inhibition of glucocerebrosidase, a lysosomal enzyme mutated in Gaucher’s disease and a main risk for Parkinson’s disease, causes lysosomal dysfunction in primary fibroblasts and contributes to the accumulation of Tau. Considering the presence of Tau lesions in Parkinson’s disease as well as in multiple neurodegenerative disorders including Alzheimer’s disease, our data call for further studies on strategies to alleviate ALP dysfunction as new therapeutic opportunity for neurodegenerative diseases and LSD.

show abstract

Tau Seeds in Extracellular Vesicles Induce Tau Accumulation in Degradative Organelles of Cells

Cited by 4 publications

References 80 publications

Tau Accumulation in Degradative Organelles is Associated to Lysosomal Stress

Tau Accumulation in Degradative Organelles is Associated to Lysosomal Stress

Extracellular vesicles and Alzheimer’s disease in the novel era of Precision Medicine: implications for disease progression, diagnosis and treatment

Tau accumulation in degradative organelles is associated to lysosomal stress

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