Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21). We developed fluorescent, morphology-based seeding assays that allow the formation of pathological tau aggregates to be measured in situ within 24 h in the presence of picomolar concentrations of tau seeds. We found that anti-tau antibodies accompany tau seeds into the cell, where they recruit TRIM21 shortly after entry. After binding, TRIM21 neutralizes tau seeds through the activity of the proteasome and the AAA ATPase p97/VCP in a similar manner to infectious viruses. These results establish that intracellular antiviral immunity can be redirected against host-origin endopathogens involved in neurodegeneration.
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http://dx.doi.org/10.1073/pnas.1607215114 | DOI Listing |
ACS Chem Neurosci
December 2024
Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, United States.
Oxidative stress is an important driver of aging and has been linked to numerous neurodegenerative disorders, including Alzheimer's disease. A key pathological hallmark of Alzheimer's are filamentous inclusions made of the microtubule associated protein Tau. Based on alternative splicing, Tau protein can feature either three or four microtubule binding repeats.
View Article and Find Full Text PDFActa Neuropathol Commun
December 2024
Laboratory of Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute, KU Leuven, Leuven, Belgium.
The accumulation of abnormal phosphorylated Tau protein (pTau) in neurons of the brain is a pathological hallmark of Alzheimer's disease (AD). PTau pathology also occurs in the retina of AD cases. Accordingly, questions arise whether retinal pTau can act as a potential seed for inducing cerebral pTau pathology and whether retinal pTau pathology causes degeneration of retinal neurons.
View Article and Find Full Text PDFMol Neurodegener
December 2024
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Background: Alzheimer's disease (AD) is characterized by the presence of neurofibrillary tangles made of hyperphosphorylated tau and senile plaques composed of beta-amyloid. These pathognomonic deposits have been implicated in the pathogenesis, although the molecular mechanisms and consequences remain undetermined. UFM1 is an important, but understudied ubiquitin-like protein that is covalently attached to substrates.
View Article and Find Full Text PDFbioRxiv
December 2024
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Pathological tau spreads throughout the brain along neuronal connections in Alzheimer's disease (AD), but the mechanisms that underlie this process are poorly understood. Given the high incidence and deleterious consequences of epileptiform activity in AD, we hypothesized neuronal hyperactivity and seizures are key factors in tau spread. To examine these interactions, we created a novel mouse model involving the cross of targeted recombination in active populations (TRAP) mice and the 5 times familial AD (5XFAD; 5X-TRAP) model allowing for the permanent fluorescent labelling of neuronal activity.
View Article and Find Full Text PDFAnn Clin Transl Neurol
December 2024
Department of Aging Neurobiology, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi, 474-8511, Japan.
Objective: Alzheimer's disease (AD) often coexists with cerebrovascular diseases. However, the impact of cerebrovascular diseases such as stroke on AD pathology remains poorly understood.
Methods: This study examines the correlation between cerebrovascular diseases and AD pathology.
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