scholarly journals Experimental evidence for the age dependence of tau protein spread in the brain

2019 ◽  
Vol 5 (6) ◽  
pp. eaaw6404 ◽  
Author(s):  
Susanne Wegmann ◽  
Rachel E. Bennett ◽  
Louis Delorme ◽  
Ashley B. Robbins ◽  
Miwei Hu ◽  
...  
Keyword(s):  
Tau Protein ◽  
Brain Region ◽  
Age Dependence ◽  
Tau Pathology ◽  
Related Factors ◽  
Age Related ◽  
Regional Vulnerability ◽  
Related Risk ◽  
Old Mice ◽  
The Brain

The incidence of Alzheimer’s disease (AD), which is characterized by progressive cognitive decline that correlates with the spread of tau protein aggregation in the cortical mantle, is strongly age-related. It could be that age predisposes the brain for tau misfolding and supports the propagation of tau pathology. We tested this hypothesis using an experimental setup that allowed for exploration of age-related factors of tau spread and regional vulnerability. We virally expressed human tau locally in entorhinal cortex (EC) neurons of young or old mice and monitored the cell-to-cell tau protein spread by immunolabeling. Old animals showed more tau spreading in the hippocampus and adjacent cortical areas and accumulated more misfolded tau in EC neurons. No misfolding, at any age, was observed in the striatum, a brain region mostly unaffected by tangles. Age and brain region dependent tau spreading and misfolding likely contribute to the profound age-related risk for sporadic AD.

scholarly journals Impairments in Brain Bioenergetics in Aging and Tau Pathology: A Chicken and Egg Situation?

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2531
Author(s):  
Amandine Grimm
Keyword(s):  
Brain Metabolism ◽  
Brain Aging ◽  
Cognitive Impairments ◽  
Tau Phosphorylation ◽  
The Body ◽  
Tau Pathology ◽  
Age Related ◽  
Energy Consuming ◽  
Effects Of Aging ◽  
The Brain

The brain is the most energy-consuming organ of the body and impairments in brain energy metabolism will affect neuronal functionality and viability. Brain aging is marked by defects in energetic metabolism. Abnormal tau protein is a hallmark of tauopathies, including Alzheimer’s disease (AD). Pathological tau was shown to induce bioenergetic impairments by affecting mitochondrial function. Although it is now clear that mutations in the tau-coding gene lead to tau pathology, the causes of abnormal tau phosphorylation and aggregation in non-familial tauopathies, such as sporadic AD, remain elusive. Strikingly, both tau pathology and brain hypometabolism correlate with cognitive impairments in AD. The aim of this review is to discuss the link between age-related decrease in brain metabolism and tau pathology. In particular, the following points will be discussed: (i) the common bioenergetic features observed during brain aging and tauopathies; (ii) how age-related bioenergetic defects affect tau pathology; (iii) the influence of lifestyle factors known to modulate brain bioenergetics on tau pathology. The findings compiled here suggest that age-related bioenergetic defects may trigger abnormal tau phosphorylation/aggregation and cognitive impairments after passing a pathological threshold. Understanding the effects of aging on brain metabolism may therefore help to identify disease-modifying strategies against tau-induced neurodegeneration.

scholarly journals Quantitative Assessment of Hippocampal Tau Pathology in AD and PART

2020 ◽  
Vol 70 (11) ◽  
pp. 1808-1811 ◽  
Author(s):  
Lei Zhang ◽  
Yankai Jiang ◽  
Jie Zhu ◽  
Huazheng Liang ◽  
Xiangyang He ◽  
...  
Keyword(s):  
Tau Protein ◽  
Quantitative Assessment ◽  
Hippocampal Formation ◽  
Selective Vulnerability ◽  
Tau Pathology ◽  
Regional Patterns ◽  
Mathematical Algorithm ◽  
Age Related ◽  
Distinguishing Features ◽  
Phosphorylated Tau Protein

Abstract To quantitatively assess the distribution pattern of hippocampal tau pathology in Alzheimer’s disease (AD) and primary age-related tauopathy (PART), we investigated the distribution of phosphorylated tau protein (AT8) in 6 anatomically defined subregions of the hippocampal formation and developed a mathematical algorithm to compare the patterns of tau deposition in PART and AD. We demonstrated regional patterns of selective vulnerability as distinguishing features of PART and AD in functionally relevant structures of the hippocampus. In AD cases, tau pathology was high in both CA1 and subiculum, followed by CA2/3, entorhinal cortex (EC), CA4, and dentate gyrus (DG). In PART, the severity of tau pathology in CA1 and subiculum was high, followed by EC, CA2/3, CA4, and DG. There are significant differences between sector DG and CA1, DG and subiculum in both AD and PART.

scholarly journals Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

2021 ◽  
Author(s):  
Nidheesh Thadathil ◽  
Evan Nicklas ◽  
Sabira Jazir ◽  
Tommy L Lewis ◽  
Arlan Richardson ◽  
...  
Keyword(s):  
Term Treatment ◽  
Short Term Treatment ◽  
Cell Death Pathway ◽  
Age Related ◽  
A Cell ◽  
The Central Nervous System ◽  
Layer V ◽  
Molecular Patterns ◽  
Old Mice ◽  
The Brain

Chronic inflammation of the central nervous system (CNS), termed neuroinflammation, is a hallmark of aging and a proposed mediator of cognitive decline associated with aging. Neuroinflammation is characterized by the persistent activation of microglia, the innate immune cells of the CNS, with damage-associated molecular patterns (DAMPs) being one of the well-known activators of microglia. Because necroptosis is a cell death pathway that induce inflammation through the release of DAMPs, we hypothesized that an age-associated increase in necroptosis contributes to increased neuroinflammation with age. The marker of necroptosis, phosphorylated form of MLKL (P-MLKL), and kinases in the necroptosis pathway (RIPK1, RIPK3, and MLKL) showed a region-specific increase in the brain with age, specifically in the cortex layer V and the CA3 region of the hippocampus of mice. Similarly, MLKL-oligomers, which causes membrane binding and permeabilization were significantly increased in the cortex and hippocampus of old mice relative to young mice. Nearly 70 to 80% of P-MLKL immunoreactivity was localized to neurons and less than 10% was localized to microglia, whereas no P-MLKL was detected in astrocytes. P-MLKL expression in neurons was detected in the soma, not in the processes. Blocking necroptosis using Mlkl-/- mice reduced markers (Iba-1 and GFAP) of neuroinflammation in the brains of old mice and short-term treatment with the necroptosis inhibitor, necrostatin-1s, reduced expression of proinflammatory cytokines, IL-6 and IL-1β, in the hippocampus of old mice. Thus, our data demonstrate for the first time that brain necroptosis increases with age and contributes to age-related neuroinflammation in mice.

scholarly journals Mechanisms of secretion and spreading of pathological tau protein

2019 ◽  
Vol 77 (9) ◽  
pp. 1721-1744 ◽  
Author(s):  
Cecilia A. Brunello ◽  
Maria Merezhko ◽  
Riikka-Liisa Uronen ◽  
Henri J. Huttunen
Keyword(s):  
Tau Protein ◽  
Molecular Mechanisms ◽  
Recent Literature ◽  
General Mechanism ◽  
Cell Transfer ◽  
Tau Pathology ◽  
Cellular Mechanisms ◽  
Brain Areas ◽  
Cell To Cell Transfer ◽  
The Brain

Abstract Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer’s disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-to-cell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.

scholarly journals Neurolinguistics Approach : A Plausible Paradigm in SLA

2014 ◽  
Vol 2 (1) ◽  
pp. 35-40
Author(s):  
Nima Shakouri ◽  
Parviz Maftoon ◽  
Ogholgol Nazari
Keyword(s):  
Second Language ◽  
Second Language Acquisition ◽  
Language Acquisition ◽  
Related Factors ◽  
Holistic Perspective ◽  
Age Related ◽  
The Impact ◽  
The Brain ◽  
Brain Change

Second language acquisition (SLA) can contribute to the changes in the brain. The paper having a holistic perspective towards the relation between brain and language asserts that the impact of SLA on the brain change is poorly studied. Moreover, claiming that the brain change is dynamic implicates the assumption that the plasticity of the brain is not merely determined by age-related factors. In this regard, experience, in general, and SLA, in particular, has a tremendous effect on the brain change. Thus, resting on the claim that SLA is respected as software and contributes to the function of brain, the paper directs the attention towards agrammatism which attracts much attention from the researchers in neurolinguists. The article also tends to cast lights upon our perceptions towards the notion of change in the brain from the neurolinguistic perspective.

scholarly journals Computational modeling of tau pathology spread reveals patterns of regional vulnerability and the impact of a genetic risk factor

2021 ◽  
Vol 7 (24) ◽  
pp. eabg6677
Author(s):  
Eli J. Cornblath ◽  
Howard L. Li ◽  
Lakshmi Changolkar ◽  
Bin Zhang ◽  
Hannah J. Brown ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Brain Regions ◽  
Spatial Proximity ◽  
Leucine Rich Repeat ◽  
Related Gene ◽  
Tau Pathology ◽  
Anatomical Connectivity ◽  
Regional Vulnerability ◽  
The Impact ◽  
The Brain

Neuropathological staging studies have suggested that tau pathology spreads through the brain in Alzheimer’s disease (AD) and other tauopathies, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute. In this study, we seed tau pathology in the brains of nontransgenic mice with AD tau and quantify pathology development over 9 months in 134 brain regions. Network modeling of pathology progression shows that diffusion through the connectome is the best predictor of tau pathology patterns. Further, deviations from pure neuroanatomical spread are used to estimate regional vulnerability to tau pathology and identify related gene expression patterns. Last, we show that pathology spread is altered in mice harboring a mutation in leucine-rich repeat kinase 2. While tau pathology spread is still constrained by anatomical connectivity in these mice, it spreads preferentially in a retrograde direction. This study provides a framework for understanding neuropathological progression in tauopathies.

scholarly journals Neuronal Models for Studying Tau Pathology

2010 ◽  
Vol 2010 ◽  
pp. 1-11
Author(s):  
Thorsten Koechling ◽  
Filip Lim ◽  
Felix Hernandez ◽  
Jesus Avila
Keyword(s):  
Tau Protein ◽  
Human Population ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Peptide ◽  
Tau Pathology ◽  
Histological Characteristics ◽  
The Brain ◽  
Phosphorylated Tau Protein ◽  
Genetically Modified Animals

Alzheimer's disease (AD) is the most frequent neurodegenerative disorder leading to dementia in the aged human population. It is characterized by the presence of two main pathological hallmarks in the brain: senile plaques containing -amyloid peptide and neurofibrillary tangles (NFTs), consisting of fibrillar polymers of abnormally phosphorylated tau protein. Both of these histological characteristics of the disease have been simulated in genetically modified animals, which today include numerous mouse, fish, worm, and fly models of AD. The objective of this review is to present some of the main animal models that exist for reproducing symptoms of the disorder and their advantages and shortcomings as suitable models of the pathological processes. Moreover, we will discuss the results and conclusions which have been drawn from the use of these models so far and their contribution to the development of therapeutic applications for AD.

scholarly journals 3D Neuronal Mitochondrial Morphology in Axons, Dendrites, and Somata of the Aging Mouse Hippocampus

2021 ◽  
Author(s):  
Julie Faitg ◽  
Clay Lacefield ◽  
Tracey Davey ◽  
Kathryn White ◽  
Ross Laws ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Cell Types ◽  
Aging Brain ◽  
Mitochondrial Morphology ◽  
Mitochondrial Network ◽  
Age Related ◽  
Mouse Hippocampus ◽  
Old Mice ◽  
The Brain

The brain′s ability to process complex informations relies on the constant supply of energy through aerobic respiration by mitochondria. Neurons contain three anatomically distinct compartments – the soma, dendrites, and projecting axons – which have different energetic and biochemical requirements, as well as different mitochondrial morphologies in cultured systems. Here we apply a quantitative three-dimensional electron microscopy approach to map mitochondrial network morphology and complexity in the mouse brain. We examine three neuronal sub–compartments – the soma, dendrites, myelinated axons – in the dentate gyrus and CA1 of the mouse hippocampus, two subregions with distinct principal cell types and functions. We also establish compartment-specific differences in mitochondrial morphology across these cell types between young and old mice, highlighting differences in age-related morphological recalibrations. Overall, these data define the nature of the neuronal mitochondrial network in the mouse hippocampus, providing a foundation to examine the role of mitochondrial morpho–function in the aging brain.

scholarly journals Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation

2020 ◽  
Author(s):  
Michael X. Henderson ◽  
Eli J. Cornblath ◽  
Howard L. Li ◽  
Lakshmi Changolkar ◽  
Bin Zhang ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Network Models ◽  
Spatial Proximity ◽  
Spatiotemporal Pattern ◽  
Diagnostic Feature ◽  
Tau Pathology ◽  
Anatomical Connectivity ◽  
Regional Vulnerability ◽  
Kinetics Of ◽  
The Brain

ABSTRACTTau pathology is a diagnostic feature of Alzheimer’s disease (AD) but is also a prominent feature of Parkinson’s disease (PD), including genetic forms of PD with mutations in leucine-rich repeat kinase 2 (LRRK2). In both diseases, tau pathology is progressive and correlates with cognitive decline. Neuropathological staging studies in humans and mouse models have suggested that tau spreads through the brain, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute to pathology spread. Further, it is unknown how mutations in the LRRK2 gene may modulate susceptibility to tau pathology’s initiation or spread. In this study, we used seed-based models of tauopathy to capture spatiotemporal patterns of pathology in mice. Following the injection of AD brain-derived tau into the brains of non-transgenic mice, tau pathology spreads progressively through the brain in a spatiotemporal pattern that is well-explained by anatomical connectivity. We validated and compared network models based on diffusion along anatomical connections to predict tau spread, estimate regional vulnerability to tau pathology, and investigate gene expression patterns related to regional vulnerability. We further investigated tau pathology spread in mice harboring a mutation in LRRK2 and found that while tau pathology spread is still constrained by anatomical connectivity, it spreads preferentially in a retrograde direction to regions that are otherwise resilient in wildtype mice. This study provides a quantitative demonstration that tau pathology spreads along anatomical connections, explores the kinetics of this spread, and provides a platform for investigating the effect of genetic risk factors and treatments on the progression of tauopathies.

scholarly journals Antisense Oligonucleotide-Mediated Reduction of HDAC6 Does Not Reduce Tau Pathology in P301S Tau Transgenic Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Antonio Valencia ◽  
Veronica L. Reinhart Bieber ◽  
Bekim Bajrami ◽  
Galina Marsh ◽  
Stefan Hamann ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Tau Protein ◽  
Antisense Oligonucleotide ◽  
Tau Phosphorylation ◽  
Histone Deacetylase 6 ◽  
Tau Pathology ◽  
Tau Aggregation ◽  
The Brain ◽  
Mediated Reduction ◽  
Tau Acetylation

Acetylation of tau protein is dysregulated in Alzheimer's Disease (AD). It has been proposed that acetylation of specific sites in the KXGS motif of tau can regulate phosphorylation of nearby residues and reduce the propensity of tau to aggregate. Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme involved in deacetylation of multiple targets, including tau, and it has been suggested that inhibition of HDAC6 would increase tau acetylation at the KXGS motifs and thus may present a viable therapeutic approach to treat AD. To directly test the contribution of HDAC6 to tau pathology, we intracerebroventricularly injected an antisense oligonucleotide (ASO) directed against HDAC6 mRNA into brains of P301S tau mice (PS19 model), which resulted in a 70% knockdown of HDAC6 protein in the brain. Despite a robust decrease in levels of HDAC6, no increase in tau acetylation was observed. Additionally, no change of tau phosphorylation or tau aggregation was detected upon the knockdown of HDAC6. We conclude that HDAC6 does not impact tau pathology in PS19 mice.

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