Santosh Jadhav

Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways

Neurodegeneration, induced by misfolded tau protein, and neuroinflammation, driven by glial cells, represent the salient features of Alzheimers disease (AD) and related human tauopathies. While tau neurodegeneration significantly correlates with disease progression, brain inflammation seems to be an important factor in regulating the resistance or susceptibility to AD neurodegeneration. Previously, it has been shown that there is a reciprocal relationship between the local inflammatory response and neurofibrillary lesions. Numerous independent studies have reported that inflammatory responses may contribute to the development of tau pathology and thus accelerate the course of disease. It has been shown that various cytokines can significantly affect the functional and structural properties of intracellular tau. Notwithstanding, anti-inflammatory approaches have not unequivocally demonstrated that inhibition of the brain immune response can lead to reduction of neurofibrillary lesions. On the other hand, our recent data show that misfolded tau could represent a trigger for microglial activation, suggesting the dual role of misfolded tau in the Alzheimers disease inflammatory cascade. On the basis of current knowledge, we can conclude that misfolded tau is located at the crossroad of the neurodegenerative and neuroinflammatory pathways. Thus disease-modified tau represents an important target for potential therapeutic strategies for patients with Alzheimers disease.

Truncated tau deregulates synaptic markers in rat model for human tauopathy

Synaptic failure and neurofibrillary degeneration are two major neuropathological substrates of cognitive dysfunction in Alzheimer’s disease (AD). Only a few studies have demonstrated a direct relationship between these two AD hallmarks. To investigate tau mediated synaptic injury we used rat model of tauopathy that develops extensive neurofibrillary pathology in the cortex. Using fractionation of cortical synapses, we identified an increase in endogenous rat tau isoforms in presynaptic compartment, and their mis-sorting to the postsynaptic density (PSD). Truncated transgenic tau was distributed in both compartments exhibiting specific phospho-pattern that was characteristic for each synaptic compartment. In the presynaptic compartment, truncated tau was associated with impairment of dynamic stability of microtubules which could be responsible for reduction of synaptic vesicles. In the PSD, truncated tau lowered the levels of neurofilaments. Truncated tau also significantly decreased the synaptic levels of Aβ40 but not Aβ42. These data show that truncated tau differentially deregulates synaptic proteome in pre- and postsynaptic compartments. Importantly, we show that alteration of Aβ can arise downstream of truncated tau pathology.

Protein truncation as a common denominator of human neurodegenerative foldopathies.

Neurodegenerative foldopathies are characterized by aberrant folding of diseased modified proteins, which are major constituents of the intracellular and extracellular lesions. These lesions correlate with the cognitive and/or motor impairment seen in these diseases. The majority of the disease modified proteins in neurodegenerative foldopathies belongs to the group of proteins termed as intrinsically disordered proteins (IDPs). Several independent studies have showed that abnormal protein processing constitutes the key pathological feature of these disorders. The current review focuses on protein truncation as a common denominator of neurodegenerative foldopathies, which is considered to be the major driving force behind the pathological metamorphosis of brain IDPs. The aim of the review is to emphasize the key role of the protein truncation in the pathogenic pathways of neurodegenerative diseases. A deeper understanding of the complex downstream processing of the IDPs, resulting in the generation of pathologically modified proteins might be a prerequisite for the successful therapeutic strategies of several fatal neurodegenerative diseases.

Tau hyperphosphorylation in synaptosomes and neuroinflammation are associated with canine cognitive impairment

Canine cognitive impairment syndrome (CDS) represents a group of symptoms related to the aging of the canine brain. These changes ultimately lead to a decline of memory function and learning abilities, alteration of social interaction, impairment of normal housetraining, and changes in sleep–wake cycle and general activity. We have clinically examined 215 dogs, 28 of which underwent autopsy. With canine brains, we performed extensive analysis of pathological abnormalities characteristic of human Alzheimers disease and frontotemporal lobar degeneration, including β‐amyloid senile plaques, tau neurofibrillary tangles, and fused in sarcoma (FUS) and TAR DNA‐binding protein 43 (TDP43) inclusions. Most demented dogs displayed senile plaques, mainly in the frontal and temporal cortex. Tau neurofibrillary inclusions were found in only one dog. They were identified with antibodies used to detect tau neurofibrillary lesions in the human brain. The inclusions were also positive for Gallyas silver staining. As in humans, they were distributed mainly in the entorhinal cortex, hippocampus, and temporal cortex. On the other hand, FUS and TDP43 aggregates were not present in any of the examined brain samples. We also found that CDS was characterized by the presence of reactive and senescent microglial cells in the frontal cortex. Our transcriptomic study revealed a significant dysregulation of genes involved in neuroinflammation. Finally, we analyzed tau phosphoproteome in the synaptosomes. Proteomic studies revealed a significant increase of hyperphosphorylated tau in synaptosomes of demented dogs compared with nondemented dogs. This study suggests that cognitive decline in dogs is related to the tau synaptic impairment and neuroinflammation. J. Comp. Neurol. 524:874–895, 2016.

Tau-mediated synaptic damage in Alzheimer’s disease

Abstract Synapses are the principal sites for chemical communication between neurons and are essential for performing the dynamic functions of the brain. In Alzheimer’s disease and related tauopathies, synapses are exposed to disease modified protein tau, which may cause the loss of synaptic contacts that culminate in dementia. In recent decades, structural, transcriptomic and proteomic studies suggest that Alzheimer’s disease represents a synaptic disorder. Tau neurofibrillary pathology and synaptic loss correlate well with cognitive impairment in these disorders. Moreover, regional distribution and the load of neurofibrillary lesions parallel the distribution of the synaptic loss. Several transgenic models of tauopathy expressing various forms of tau protein exhibit structural synaptic deficits. The pathological tau proteins cause the dysregulation of synaptic proteome and lead to the functional abnormalities of synaptic transmission. A large body of evidence suggests that tau protein plays a key role in the synaptic impairment of human tauopathies.

Human Truncated Tau Induces Mature Neurofibrillary Pathology in a Mouse Model of Human Tauopathy

Alzheimers disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151-391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy.

Of Rodents and Men: The Mysterious Interneuronal Pilgrimage of Misfolded Protein Tau in Alzheimer's Disease

Neurofibrillary degeneration, driven by misfolded protein tau, spreads from the predisposed induction sites and advances in a topographically predictable sequence along connected brain areas. Several mouse model studies have demonstrated that some species of pathologically modified tau, namely insoluble fibrils and soluble oligomers, evoke propagation of the pathology. These results clearly show that the spreading potency of misfolded tau does not depend exclusively on its solubility and/or mutations. The candidate factor responsible for the progression of misfolded protein tau is its disease modified conformation. In this study, we address the question, whether insoluble tau complexes containing either 3R or 4R human misfolded truncated tau (AlzTau) command distinct infectivity and spreading potency. We found that insoluble tau isolated from transgenic rats (SHR24), expressing misfolded 3R AlzTau, was able to infect cortical neurons in the area of injection in SHR72 transgenic rats expressing 4R AlzTau. However this tau was not able to spread into other brain areas. In contrast, administration of insoluble tau isolated from SHR72 transgenic rats was not only able to infect cortical neurons but also induced extensive spreading of neurofibrillary tangles in the adjacent brain areas. These findings suggest the existence of various strains of disease modified tau, tauons displaying different infectivity and spreading potency. Furthermore, the presented rat tauopathy models could serve as a tool for identification and characterization of tauons isolated from Alzheimers disease brains that would allow stratification of Alzheimers disease patients.

Dendritic Cells as an Alternate Approach for Treatment of Neurodegenerative Disorders

Despite years of research, Alzheimer’s disease (AD) remains incurable and thus poses a major health challenge in coming years. This neurodegenerative disease belongs to a heterogeneous group of human tauopathies, characterized by the extracellular deposition of beta amyloid-Aβ and intracellular accumulation of tau protein in neuronal and glial cells, whereby tau pathology best correlates with disease progression. For decades, several disease-modifying agents were brought to clinical studies with promising efficacy in preclinical trials; however, all of the subsequent clinical trials failed. Therefore, the pursuit for therapeutic agents for the treatment of AD and other tauopathies still continue. Recent evidences show previously unidentified role of peripheral immune system in regulating the inflammatory status of the brain, mainly the dendritic cells. A decrease in functionality and count of dendritic cells has been observed in Alzheimer’s disease. Here, we discuss a potential role of dendritic cell-based vaccines as therapeutic approach in ameliorating disease pathogenesis in AD and other tauopathies.

Transmission of Tau Pathology from Human to Rodent Brain: How to Humanise Animal Models for Alzheimer’s Disease Research

Tauopathies represent a group of neurodegenerative disorders characterised by the accumulation of conformationally altered tau protein. Alzheimer’s disease (AD) is the most prevalent primary tauopathy. In AD, tau pathology progressively spreads across a stereotypical sequence of anatomically connected brain regions. In early stages, the disease manifests in the locus coeruleus and entorhinal cortex; at later stages it spreads through the hippocampus to cortical brain areas. Recent studies suggest that spreading of pathological tau occurs predominantly through neuron-to-neuron transmission; however, glial cells can also be involved in this process. Propagation depends on the conformational state and post-translational modifications of tau protein of various tau strains. Abnormal tau can subsequently act as a seed, misfolding and aggregating normal tau proteins inside the cells. Several research groups have successfully recapitulated tau transmission in animal models. Currently, we are able to induce and drive tau neurodegeneration by using tau species isolated from diseased human brains. Such state-of-the-art “humanised” animal models represent a powerful tool for development of new drug leads and diagnostics for human tauopathies.

Neuronal Expression of Truncated Tau Efficiently Promotes Neurodegeneration in Animal Models: Pitfalls of Toxic Oligomer Analysis

Animal models of neurodegeneration induced by neuronal expression of truncated tau protein emerge as an important tool for understanding the pathogenesis of human tauopathies and for therapy development. Here we highlight common features of truncated tau models and make a critical assessment of possible pitfalls in their analysis. Particularly, the amount of soluble tau oligomers, which are suspected to be neurotoxic agents participating on the spreading of pathology inside the brain, may be overestimated due to a post-lysis oxidative tau oligomerization. Using a mouse brain lysate spiked with recombinant truncated and full length tau forms, we show that tau oligomers might inadvertently be produced during the isolation procedure. This finding is further corroborated by the analysis of brain lysates originated from a mouse model expressing truncated tau variant. Our results underline the necessity of thiol-protecting conditions during the analysis of tau oligomers involved in the etiopathogenesis of various tauopathies including Alzheimers disease.