The Down-Regulation of Clusterin Expression Enhances the αSynuclein Aggregation Process

Lenzi, Carla; Ramazzina, Ileana; Russo, Isabella; Filippini, Alice; Bettuzzi, Saverio; Rizzi, Federica

doi:10.3390/ijms21197181

Cited by 19 publications

(17 citation statements)

References 53 publications

(61 reference statements)

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“…In the case of α-Syn, another amyloidogenic protein that undergoes prion-like aggregate spreading 1 , Clu blocked both aggregation and seeding (Fig. 6e), consistent with recent observations 64, 75, 76 . Indeed, Clu is upregulated in PD and other synucleinopathies 77 .…”

Section: Discussionsupporting

confidence: 91%

The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

Yuste-Checa

Trinkaus

Riera-Tur

et al. 2021

Preprint

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Spreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimer's disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naive cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.

show abstract

Section: Discussionsupporting

confidence: 91%

The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

Yuste-Checa

Trinkaus

Riera-Tur

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…In the case of α-Syn, another amyloidogenic protein that undergoes prion-like aggregate spreading 1 , Clu blocked both aggregation and seeding (Fig. 6e), consistent with recent observations 64,75,76 . Indeed, Clu is upregulated in PD and other synucleinopathies 77 .…”

Section: Discussionsupporting

confidence: 89%

The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

et al. 2021

View full text Add to dashboard Cite

Spreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimer’s disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naïve cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.

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“…Modulates NF-κB (NF-κB implicated in adult neurogenesis and structural plasticity). (Essabbani et al, 2010;see Foster et al, 2019;Kogel et al, 2012;Lenzi et al, 2020;Xu et al, 2008)…”

Section: Trem2mentioning

confidence: 99%

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

Murphy¹

2021

Preprint

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Alzheimer’s Disease is defined as progressive memory loss coincident with accumulation of aggregated amyloid beta and phosphorylated tau. Identifying the relationship between these features has guided Alzheimer’s Disease research for decades, principally with the view that aggregated proteins drive a neurodegenerative process. Here I propose that amyloid beta and phospho-tau write-protect and tag neuroplastic changes as they form, protecting and insuring established neuroplasticity from corruption. In way of illustration, binding of oligomeric amyloid beta to the prion receptor is presented as an example possible mechanism. The write-protecting process is conjected to occur at least partially under the governance of isodendritic neuromodulators such as norepinephrine and acetylcholine. Coincident with aging, animals are exposed to accumulating amounts of memorable information. Compounded with recent increases in life expectancy and exposure to information-rich environments this causes aggregating proteins to reach unforeseen toxic levels as mnemonic circuits overload. As the brain cannot purposefully delete memories nor protect against overaccumulation of aggregating proteins, the result is catastrophic breakdown on cellular and network levels causing memory loss.

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The Down-Regulation of Clusterin Expression Enhances the αSynuclein Aggregation Process

Cited by 19 publications

References 53 publications

The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

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