Dataset Information

Tau-Mediated Dysregulation of Neuroplasticity and Glial Plasticity.

ABSTRACT: The inability of individual neurons to compensate for aging-related damage leads to a gradual loss of functional plasticity in the brain accompanied by progressive impairment in learning and memory. Whereas this loss in neuroplasticity is gradual during normal aging, in neurodegenerative diseases such as Alzheimer's disease (AD), this loss is accelerated dramatically, leading to the incapacitation of patients within a decade of onset of cognitive symptoms. The mechanisms that underlie this accelerated loss of neuroplasticity in AD are still not completely understood. While the progressively increasing proteinopathy burden, such as amyloid ? (A?) plaques and tau tangles, definitely contribute directly to a neuron's functional demise, the role of non-neuronal cells in controlling neuroplasticity is slowly being recognized as another major factor. These non-neuronal cells include astrocytes, microglia, and oligodendrocytes, which through regulating brain homeostasis, structural stability, and trophic support, play a key role in maintaining normal functioning and resilience of the neuronal network. It is believed that chronic signaling from these cells affects the homeostatic network of neuronal and non-neuronal cells to an extent to destabilize this harmonious milieu in neurodegenerative diseases like AD. Here, we will examine the experimental evidence regarding the direct and indirect pathways through which astrocytes and microglia can alter brain plasticity in AD, specifically as they relate to the development and progression of tauopathy. In this review article, we describe the concepts of neuroplasticity and glial plasticity in healthy aging, delineate possible mechanisms underlying tau-induced plasticity dysfunction, and discuss current clinical trials as well as future disease-modifying approaches.

SUBMITTER: Koller EJ

PROVIDER: S-EPMC7472665 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Tau-Mediated Dysregulation of Neuroplasticity and Glial Plasticity.

Koller Emily J EJ Chakrabarty Paramita P

Frontiers in molecular neuroscience 20200821

The inability of individual neurons to compensate for aging-related damage leads to a gradual loss of functional plasticity in the brain accompanied by progressive impairment in learning and memory. Whereas this loss in neuroplasticity is gradual during normal aging, in neurodegenerative diseases such as Alzheimer's disease (AD), this loss is accelerated dramatically, leading to the incapacitation of patients within a decade of onset of cognitive symptoms. The mechanisms that underlie this accel ...[more]

PMID: 32973446

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Project description:Tauopathies are neurodegenerative disorders characterized by aggregation of microtubule associated tau protein in neurons and glia. They are clinically and pathologically heterogeneous depending on the isoform of tau protein that accumulates (three or four 31-to-32-amino-acid repeats [3R or 4R] in the microtubule binding domain), as well as the cellular and neuroanatomical distribution of tau pathology. Growing evidence suggests that distinct tau conformers may contribute to the characteristic features of various tauopathies. Globular glial tauopathy (GGT) is a rare 4R tauopathy with globular cytoplasmic inclusions within neurons and glial cells. Given the unique cellular distribution and morphology of tau pathology in GGT, we sought to determine if tau species in GGT had distinctive biological properties. To address this question, we performed seeding analyses with postmortem brain tissues using a commercial tau biosensor cell line. We found that brain lysates from GGT cases had significantly higher seeding competency than other tauopathies, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD). The robust seeding activity of GGT brain lysates was independent of phosphorylated tau burden and diminished upon removal of tau from samples, suggesting that seeding properties were indeed mediated by tau in the lysates. In addition, cellular inclusions in the tau biosensor cell line induced by GGT had a distinct, globular morphology that was markedly different from inclusions induced by other tauopathies, further highlighting the unique nature of tau species in GGT. Characterization of different tau species in GGT showed that detergent-insoluble, fibril-like tau contained the highest seeding activity, as reflected in its ability to increase tau aggregation in primary glial cultures. Taken together, our data suggest that unique seeding properties differentiate GGT-tau from other tauopathies, which provides new insight into pathogenic heterogeneity of primary neurodegenerative tauopathies.

Project description:Active Caspase-6 (Casp6) and Tau cleaved by Casp6 at amino acids 402 (Tau∆D402) and 421 (Tau∆D421) are present in early Alzheimer disease intraneuronal neurofibrillary tangles, which are made primarily of filamentous Tau aggregates. To assess whether Casp6 cleavage of Tau contributes to Tau pathology and Casp6-mediated age-dependent cognitive impairment, we generated transgenic knock-in mouse models that conditionally express full-length human Tau (hTau) 0N4R only (CTO) or together with human Casp6 (hCasp6) (CTC). Region-specific hippocampal and cortical hCasp6 and hTau expression were confirmed with western blot and immunohistochemistry in 2-25-month-old brains. Casp6 activity was confirmed with Tau∆D421 and Tubulin cleaved by Casp6 immunopositivity in 3-25-month-old CTC, but not in CTO, brains. Immunoprecipitated Tau∆D402 was detected in both CTC and CTO brains, but was more abundant in CTC brains. Intraneuronal hippocampal Tau hyperphosphorylation at S202/T205, S422, and T231, and Tau conformational change were absent in both CTC and CTO brains. A slight accumulation of Tau phosphorylated at S396/404 and S202 was observed in Cornu Ammonis 1 (CA1) hippocampal neuron soma of CTC compared to CTO brains. Eighteen-month-old CTC brains showed rare argentophilic deposits that increased by 25 months, whereas CTO brains only displayed them sparsely at 25 months. Tau microtubule binding was equivalent in CTC and CTO hippocampi. Episodic and spatial memory measured with novel object recognition and Barnes maze, respectively, remained normal in 3-25-month-old CTC and CTO mice, in contrast to previously observed impairments in ACL mice expressing equivalent levels of hCasp6 only. Consistently, the CTC and CTO hippocampal CA1 region displayed equivalent dendritic spine density and no glial inflammation. Together, these results reveal that active hCasp6 co-expression with hTau generates Tau cleavage and rare age-dependent argentophilic deposits but fails to induce cognitive deficits, neuroinflammation, and Tau pathology.

Dataset Information

Tau-Mediated Dysregulation of Neuroplasticity and Glial Plasticity.

Publications

Tau-Mediated Dysregulation of Neuroplasticity and Glial Plasticity.

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