Tauopathies

Central insulin resistance is a typical trait associated with premature ageing and is shown in neurological illnesses such as Alzheimer’s disease (AD) in its early stages. In this sense, the (phosphoinositide 3 kinase)/Akt pathway mediates insulin signalling in the brain, where defective insulin signalling is a risk factor for developing AD. Several lines of evidence show that integrated coordination of neuronal responses through the PI3K /Akt pathway in the brain has a significant functional impact on key events that are negatively affected in AD. Moreover, the PIK3/Akt pathway is crucial in

In several neurodegenerative diseases, commonly referred to as tauopathies, pathological forms of the microtubule-associated protein tau spread in a prion-like manner from donor cells to surrounding (recipient) cells, which clinically correlates with the progressive decline in cognition and cell death. Low density lipoprotein receptor-related protein 1 (LRP1) regulates the endocytosis of tau in neurons and thus its subsequent spread. This LRP1-mediated endocytosis is depended upon regulation of actin. The major regulator of actin filament dynamics is tropomyosin, a family of proteins, shown to

…These tauopathies exhibit distinct tau isoform profiles, with primary tauopathies such as PiD predominantly featuring 3R tau, while secondary tauopathies like AD involve both 3R and 4R isoforms. Recent scientific investigations have uncovered the impact of tau alterations, including overexpression and hyperphosphorylation, on chromatin structure. In this study, we present a comprehensive analysis of epigenomic

…neurodegenerative diseases, like tauopathies, can significantly alter SNA. Changes in SNA after the expression of tau mutations have not yet been analysed at presymptomatic stages. Furthermore, the currently available models lack the necessary complexity of the human brain to fully understand the underlying mechanisms of tau pathology and its effects on SNA. To address this, we present a novel in vitro platform utilizing cortical organoids (COs), derived from hPSCs, to

Tauopathies are leading cause of loss of autonomy in the elderly, implying a progressive cognitive decline. There is not an effective treatment early diagnosis of tauopathies. We propose an in-vitro and theragnostic approach by using a novel phosphorylated Tau(p-Tau) monoclonal antibody(mAb) responsible for tau self-aggregation and regulation.A diagnostic Sandwich ELISA kit was developed and tested in 89 cerebrospinal fluid (CSF) samples of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) patients for detection of p-Tau.The proof of concept study reported specific signals above the

Alzheimer’s disease (AD), which is characterized by extracellular accumulation of amyloid-beta peptide and intracellular aggregation of hyperphosphorylated tau, is the most common form of dementia. During AD pathogenesis, tau is abnormally phosphorylated and aggregating within neurons. As a result of continuous intraneuronal tau aggregation, neurofibrillary tangles are formed. The aim of our project is to determine, whether inhibiting tau protein aggregation with a novel anti-aggregative compound “RE01” improves survival, behavior and neuropathology in a tau-transgenic mouse model. RE01 is an

Tau accumulation is clearly linked to pathogenesis in Alzheimer’s disease and other Tauopathies. However, processes leading to Tau fibrillization and reasons for its pathogenicity remain largely elusive. Mical emerged as a novel interacting protein of human Tau expressed in Drosophila brains. Mical is characterized by the presence of a flavoprotein monooxygenase domain that generates redox potential with which it can oxidize target proteins. In the well-established Drosophila Tauopathy model, we use genetic interactions to show that Mical alters Tau interactions with microtubules and the Actin

…of Alzheimer’s disease and other tauopathies. By doing so, we wanted to evaluate molecules capable of preventing tau-mediated neurodegeneration. To achieve this, we established cultures of mouse cortical neurons in which hyperphosphorylated (but not aggregated) tau accumulates in a significant population of neurons following chronic exposure to redox-active iron from hemin (Hm), a breakdown product of hemoglobin. Using experimental conditions in which p-tau (AT8 immunosignal) accumulation occurs without concomitant neuronal l

…hallmarks for synucleinopathies and tauopathies, respectively. Co-occurrence of a-Syn and tau aggregates was found in the post-mortem brains of the patients, suggesting a complex interplay between two proteins contributes to the diseases. Here, we explore the polymorphism of α-Syn and Tau cross-seeding with a correlative approach combining fluorescent and super-resolution optical photothermal infrared (O-PTIR) imaging. We first show that hybrid α-Syn-Tau 0N3R pre-formed fibrils (PFFs) form more amyloid-rich structures than α-Syn or a-S

Mutations in the MAPT gene encoding tau protein cause neurodegenerative tauopathies. Recently, PET imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration remain largely unknown. In this study, we examined post-mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by the MAPT intronic exon 10+16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule binding domains. We used

Early changes in network activity serve as distinctive hallmarks in tauopathies such as Alzheimer’s Disease and Frontotemporal Dementia. Decades before the onset of cognitive decline, many patients experience seizures which exacerbate the condition. Despite the recognised etiological overlaps between tauopathies and epilepsies, the relationship between tau and the development of circuit hyperexcitability is unclear and needs further investigation. Using wireless EEG to record intrahippocampal local field potentials (LFP), we characterised early biophysical alterations within the hippocampus of

…cell death in Alzheimer’s disease and tauopathies. While there has been progress uncovering mechanisms leading to the formation of toxic Tau tangles, less is known about how intraneuronal Tau levels are regulated in health and disease. Here, I will discuss our recent work showing that the intracellular trafficking adaptor protein Numb is critical to control intraneuronal Tau levels. Inactivation of Numb in retinal ganglion cells increases monomeric and olig

Protein quality control is essential for maintenance of a healthy and functional proteome that can attend the multiplicity of cellular functions. Failure of the systems that contribute to protein homeostasis, the so called proteostasis networks, have been identified in the pathogenesis of multiple neurodegenerative disorders and demonstrated to contribute to disease onset and progression. We are interested in autophagy, one of the components of the proteostasis network, and in the interplay of wo selective types of autophagy, chaperone-mediated autophagy (CMA) and endosomal microautophagy (eM

…as a key mediator of neuronal death in tauopathies, a group of neurodegenerative disorders that are pathologically characteri