Tau protein aggregation: A therapeutic target for neurodegenerative diseases.

Accelerated Human Mutant Tau Aggregation by Knocking Out Murine Tau in a Transgenic Mouse Model

Classification of diseases with accumulation of Tau protein.

Amyloid Activates GSK-3β to Aggravate Neuronal Tauopathy in Bigenic Mice

The Synaptic Accumulation of Hyperphosphorylated Tau Oligomers in Alzheimer Disease Is Associated With Dysfunction of the Ubiquitin-Proteasome System

Cholesterol, a principal constituent of the cell membrane, plays a crucial role in the brain by regulating the synaptic transmission, neuronal signaling, as well as neurodegenerative diseases. Defects in the cholesterol trafficking are associated with enhanced generation of hyperphosphorylated Tau and Amyloid-β protein. Tau, a major microtubule-associated protein in the brain, is the key regulator of the mature neuron. Abnormally hyperphosphorylated Tau hampers the major functions related to microtubule assembly by promoting neurofibrillary tangles of paired helical filaments, twisted ribbons, and straight filaments. The observed pathological changes due to impaired cholesterol and Tau protein accumulation cause Alzheimer's disease. Thus, in order to regulate the pathogenesis of Alzheimer's disease, regulation of cholesterol metabolism, as well as Tau phosphorylation, is essential. The current review provides an overview of (1) cholesterol synthesis in the brain, neurons, astrocytes, and microglia; (2) the mechanism involved in modulating cholesterol concentration between the astrocytes and brain; (3) major mechanisms involved in the hyperphosphorylation of Tau and amyloid-β protein; and (4) microglial involvement in its regulation. Thus, the answering key questions will provide an in-depth information on microglia involvement in managing the pathogenesis of cholesterol-modulated hyperphosphorylated Tau protein.

Alzheimer’s disease and Parkinson’s disease are characterized by distinct types of abnormal protein aggregates within neurons. These aggregates are known as neurofibrillary tangles and Lewy bodies, which consist of tau and α-synuclein, respectively. As the diseases progress, these aggregates spread from one cell to another, causing protein pathology to affect broader regions of the brain. Another notable characteristic of these diseases is neuroinflammation, which occurs when microglia become activated. Recent studies have suggested that inflammation may contribute to the formation and propagation of protein aggregates. However, it remains unclear whether microglia-driven inflammation can initiate and propagate different proteinopathies and associated neuropathology in neurodegenerative diseases. Here, using single-cell RNA sequencing, we observed that microglia exposed to α-synuclein or tau underwent changes in their characteristics and displayed distinct types of inflammatory response. The naive mice that received these microglial cell transplants developed both tauopathy and synucleinopathy, along with gliosis and inflammation. Importantly, these pathological features were not limited to the injection sites but also spread to other regions of the brain, including the opposite hemisphere. In conjunction with these pathological changes, the mice experienced progressive motor and cognitive deficits. These findings conclusively demonstrate that microglia-driven inflammation alone can trigger the full range of pathological features observed in neurodegenerative diseases, and that inflammation-induced local neuropathology can spread to larger brain regions. Consequently, these results suggest that microglia-driven inflammation plays an early and pivotal role in the development of neurodegenerative diseases.The transplantation of microglia activated by αSyn or tau proteins into the brains of naive mice resulted in the formation of synucleinopathy, tauopathy, gliosis, neuroinflammation and behavioral abnormalities. Activated microglia displayed alterations in subclusters as well as the corresponding feature genes.

Alzheimer's disease (AD) represents a significant challenge in neurodegenerative disorders, characterized by the accumulation of amyloid-beta (Aβ) plaques and tau protein tangles in the brain. Current treatments provide symptomatic relief but do not halt disease progression. ganoderic acid A, derived from Ganoderma lucidum, has shown to act as a dual inhibitor of Aβ and tau protein aggregation through in vitro and animal model studies. This study aims to explore the therapeutic potential of ganoderic acid A using in silico methods to predict its binding affinity and mode of interaction with Aβ and tau proteins. Analysis included molecular docking simulations using computational models to evaluate the binding of ganoderic acid A to Aβ and tau proteins. Various tools were employed to predict the binding energy, interaction sites (Autodock), and MD (CABSflex 2.0) of these complexes. Ganoderic acid A demonstrated favorable binding energies and interactions with both Aβ and tau proteins. The compound exhibited potential dual inhibition capabilities by forming stable complexes with critical residues involved in Aβ aggregation and tau protein hyperphosphorylation. The findings suggest that ganoderic acid A holds promise as a dual inhibitor of Aβ and tau protein aggregation in AD. By targeting these key pathological processes, ganoderic acid A may offer therapeutic benefits in halting or slowing disease progression. Confirming these predictions and advancing ganoderic acid A as a possible AD treatment will require additional experimental validation, including in vitro and in vivo research.

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI), and over twenty others. Tau‐containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss (Arriagada, Growdon, Hedley‐Whyte, & Hyman, 1992), yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis (de Calignon, Spires‐Jones, Pitstick, Carlson, & Hyman, 2009), which suggests that secondary mechanisms are driving toxicity. Transcriptomic analyses of NFT‐containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction. Using four AD transgenic mouse models, we found that NFTs, but not Aβ plaques, display a senescence‐like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late‐stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.

Alzheimer's Disease-Like Tau Neuropathology Leads to Memory Deficits and Loss of Functional Synapses in a Novel Mutated Tau Transgenic Mouse without Any Motor Deficits

Old cats : a naturally occuring model of tauopathy.

Chapter 8 - Alkaloids as Potential Multi-Target Drugs to Treat Alzheimer's Disease

Utilisation des algues marines: Par Camille Sauvageau. Professor in the Faculty of Science, Bordeaux. 12mo., 356 pages, bibliography, contents, indexes and 26 illustrations.Paris, Gaston Doin. 9 francs

Neurodegenerative disorders are morphologically featured by progressive cell loss in specific vulnerable neuronal populations of the brain and/or spinal cord, often associated with typical cytoskeletal protein changes forming intracytoplasmic and/or intra-nuclear inclusions and gliosis. In Alzheimer’s disease (AD), the most common type of dementia in advanced age, loss of cortical neurons and synapses is accompanied by extracellular deposition of Aβ4 amyloid peptide (Aβ) in senile plaques and cerebral vessels. Paired helical filaments containing hyperphosphorylated microtubule-associated tau protein forming neurofibrillary tangles (NFT), neuropil threads, and neuritic plaques are other histopathological hallmarks of AD (1). In Parkinson’s disease (PD), the most frequent extrapyramidal movement disorder in adults, neuron loss in substantia nigra (SN) and other subcortical nuclei is associated with widespread occurrence of intracytoplasmic Lewy bodies (LB) formed from fibrillary α-synuclein and hyperphosphorylated neurofilament protein (2–5). Frequent cortical LBs occur in dementia with Lewy bodies (DLB), which is the second most frequent type in adult age dementia (6), but small numbers are also seen in both PD and AD (7,8). In Pick disease (PiD), a rare presenile type of frontotemporal dementia (FTD), progressive cortical degeneration is associated with Pick bodies, intracytoplasmic accumulations of hyperphosphorylated tau protein (9–11). In multisystem atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), which are rigid-akinetic extrapyramidal disorders, multisystemic neuronal degeneration is accompanied by glial cytoplasmic inclusions (GCI) containing tau protein that differs from that in AD and PiD (2,10,11) and a-synuclein (12). In Huntington disease (HD), an autosomal dominantly inherited hyperkinetic extrapyramidal disorder resulting from mutation of the IT-15 gene on chromosome 4p16.3 with expanded polyglutamine CAG repeats, neurodegeneration in man and transgenic mice is related to neuronal intranuclear inclusions containing huntingtin and ubiquitin (13,14). Similar inclusions are seen in other rare autosomal dominant ataxic polyglutamine disorders (e.g., dentatorubropallidoluysian atrophy [DRPLA]), suggesting that these protein aggregates are a common feature of the pathogenesis of glutamine repeat neurodegenerations (13,15). In amyotrophic lateral sclerosis (ALS), which is an adult neurodegenerative disease of both lower and upper motor neurons, skein-like ubiquitin-containing inclusions are seen (16). The nature, time-course, and molecular causes of cell death and their relation to abnormal cytoskeletal protein aggregations, in these and other neurodegenerative disorders, are a matter of considerable controversy. Recent studies have provided new insights into cell death programs and their roles in neurodegeneration that will be discussed in this chapter.

New unexpected role for Wolfram Syndrome protein WFS1: a novel therapeutic target for Alzheimer's disease?

Phosphorylation of Tau protein and binding to microtubules is complex in neurons and was therefore studied in the less complicated model of humanized yeast. Human Tau was readily phosphorylated at pathological epitopes, but in opposite directions regulated by kinases Mds1 and Pho85, orthologues of glycogen synthase kinase-3beta and cdk5, respectively (1). We isolated recombinant Tau-4R and mutant Tau-P301L from wild type, Delta mds1 and Delta pho85 yeast strains and measured binding to Taxol-stabilized mammalian microtubules in relation to their phosphorylation patterns. Tau-4R isolated from yeast lacking mds1 was less phosphorylated and bound more to microtubules than Tau-4R isolated from wild type yeast. Paradoxically, phosphorylation of Tau-4R isolated from kinase Pho85-deficient yeast was dramatically increased resulting in very poor binding to microtubules. Dephosphorylation promoted binding to microtubules to uniform high levels, excluding other modifications. Isolated hyperphosphorylated, conformationally altered Tau-4R completely failed to bind microtubules. In parallel to Tau-4R, we expressed, isolated, and analyzed mutant Tau-P301L. Total dephosphorylated Tau-4R and Tau-P301L bound to microtubules very similarly. Surprisingly, Tau-P301L isolated from all yeast strains bound to microtubules more extensively than Tau-4R. Atomic force microscopy demonstrated, however, that the high apparent binding of Tau-P301L was due to aggregation on the microtubules, causing their deformation and bundling. Our data explain the pathological presence of granular Tau aggregates in neuronal processes in tauopathies.