P3-204: Degradation of truncated tau protein in transgenic rat cortical neurons and human cellular model of tauopathy and Alzheimer's disease is enhanced by HSP90 inhibitors

We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurotoxicity involving Membrane Attack Complex (MAC) formation, we assessed the effects of immunocaptured AEVs (using anti-GLAST antibody), in comparison with neuronal-origin (N)EVs (using anti-L1CAM antibody), and nonspecific CD81+ EVs (using anti-CD81 antibody), from the plasma of AD, frontotemporal lobar degeneration (FTLD), and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons (by immunohistochemistry), membrane disruption (by EthD-1 assay), reduced neurite density (by Tuj-1 immunohistochemistry), and decreased cell viability (by MTT assay) in rat cortical neurons and human iPSC-derived neurons. Demonstration of decreased cell viability was replicated in a separate cohort of autopsy-confirmed AD patients. These effects were not produced by CD81+ EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and should motivate future studies on the roles of neuronal MAC deposition and AEV/NEV uptake, as effectors of neurodegeneration in AD.

Download Full-text

Astrocyte- and neuron-derived extracellular vesicles from Alzheimer’s disease patients effect complement-mediated neurotoxicity

10.1101/2020.04.14.041863 ◽

2020 ◽

Author(s):

Carlos J Nogueras-Ortiz ◽

Vasiliki Mahairaki ◽

Francheska Delgado-Peraza ◽

Debamitra Das ◽

Konstantinos Avgerinos ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Extracellular Vesicles ◽

Cortical Neurons ◽

Membrane Attack Complex ◽

Neurite Density ◽

Complement Inhibitors ◽

Rat Cortical Neurons ◽

And Control ◽

Human Ipsc

AbstractWe have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurodegeneration, we assessed the neurotoxicity of immunocaptured AEVs (with anti-GLAST antibody), neuronal-origin NEVs (with anti-L1CAM antibody), and multicellular-origin (with anti-CD81 antibody) EVs from the plasma of AD, frontotemporal lobar degeneration (FTLD) and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons, membrane disruption, reduced neurite density, and decreased cell viability in rat cortical neurons and human IPSC-derived neurons. Neurodegenerative effects were not produced by multicellular-origin EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and suggest that neuronal MAC deposition is necessary for AEV/NEV-mediated neurodegeneration in AD.

Download Full-text

Phosphorylated tau protein as a core biomarker of Alzheimer’s disease

Pharmacopsychiatry ◽

10.1055/s-2003-825356 ◽

2004 ◽

Vol 36 (05) ◽

Author(s):

H Hampel

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Protein ◽

Phosphorylated Tau ◽

Phosphorylated Tau Protein

Download Full-text

Molecular Docking Studies on Evolvulus Alsinoides Compounds Against TAU Protein in Alzheimer’s Disease

International Journal of Scientific Research ◽

10.15373/22778179/jan2014/7 ◽

2012 ◽

Vol 3 (1) ◽

pp. 21-24

Author(s):

Darsi Vanaja ◽

◽

Kuna Yellamma

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Docking ◽

Tau Protein ◽

Docking Studies ◽

Molecular Docking Studies ◽

Evolvulus Alsinoides

Download Full-text

Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer's Disease

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200106125910 ◽

2020 ◽

Vol 20 (12) ◽

pp. 1059-1073 ◽

Cited By ~ 3

Author(s):

Ahmad Abu Turab Naqvi ◽

Gulam Mustafa Hasan ◽

Md. Imtaiyaz Hassan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Protein ◽

Glycogen Synthase ◽

Paired Helical Filaments ◽

Tau Hyperphosphorylation ◽

Microtubule Stabilization ◽

Extracellular Signal

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 β (GSK3β), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer's disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

Download Full-text

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

Nature Communications ◽

10.1038/s41467-021-25060-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Patricia Yuste-Checa ◽

Victoria A. Trinkaus ◽

Irene Riera-Tur ◽

Rahmi Imamoglu ◽

Theresa F. Schaller ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Progression ◽

Frontotemporal Dementia ◽

Brain Regions ◽

Model System ◽

Cellular Model ◽

Tau Pathology ◽

Extracellular Chaperone ◽

Tau Aggregate

AbstractSpreading 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.

Download Full-text