Tau

…interacts with amyloid, tau and synaptic dysfunction in brain and biofluids. The postdoc works on a multi-tracer in vivo PET study measuring amyloid and tau deposition, astrogliosis and synapse impairment together with cognitive tests, CSF, plasma biomarke

…lead projects on cellular senescence, tau biology and their roles in neurodegenerative disease. The scientist co-designs and executes studies at the intersection of biological aging and neurodegeneration; develops cellular, molecular, biochemical and imaging techniques to study brain aging; leads projects across cells, animal models, postmortem human tissue and clinical trials; works with clinicians, computational biologists and neuroscientists; mentors postdocs, graduate students and technicians; contributes to gra

…evidence concerning phosphorylated tau and herpesvirus activity. The episode connects ancient molecular recognition mechanisms with questions about antiviral defence.

…by the accumulation of Aβ and Tau proteins. While many animal models primarily focus on Aβ, this study centers on characterizing a tauopathy model, the PS19 model (B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J), to explore the pathological role of tau in AD.36 PS19 and 24 non-carrier mice (NCAR) were followed from 12 to 50 weeks, assessing locomotor, behavior, and memory activity, neurodegeneration, neuroinflammation, blood-brain barrier (BBB) integrity, cerebral glucose metabolism, and neurodegenerative progression

…as Beta-amyloid, Alpha-synuclein and Tau aggregation within synapses, remains limited. To address this, we present a novel method for visualizing protein aggregates in individual synaptosomes. We combined Single-molecule Pull Down (SiMPull) and direct Stochastic Optical Reconstruction Microscopy (dSTORM), to immobilize individual synaptosomes and characterize single aggregates within them with ~20nm spatial resolution

In Alzheimer’s Disease (AD), memory deficits, particularly in spatial tasks, are well-documented. However, integrated memory encompassing both spatial and social information remains less explored. This study investigates early impairments in social recognition in the triple transgenic murine model of AD (3xTgAD) and correlates these deficits with the progression of AD pathology. Female 3xTgAD mice aged 2-4 and 6-8 months underwent a social recognition test, revealing significant impairments in recognizing non-familiar individuals by 6-8 months. Immunofluorescence assays for beta-amyloid and TA

Tau, is an intrinsically disordered protein crucial for stabilizing and polymerizing microtubules (MTs). However, in Alzheimer's disease (AD), Tau undergoes hyperphosphorylation, leading to its misfolding and detachment from MTs, forming droplets termed liquid-liquid phase separation (LLPS), believed to be a precursor to Tau aggregates. Despite being a biomarker for AD, the role of AT8 phosphorylation (S202, T205, and S208) in Tau spread and toxicity remains unclear. To address this issue, we generated Tau variants with different AT8 phosphorylation states: PTau 2A-, 208- (lacking AT8 phosphor

The microtubule-associated protein tau plays a critical role in many neurodegenerative diseases, including Alzheimer’s disease. Abnormal hyperphosphorylation of tau (pTau) generates pathological paired helical filaments (PHF) that aggregate into neurofibrillary tangles, which leads to a cascade of changes including neuroinflammation and network excitability. Abnormal pTau, neuroinflammation, and seizures also occur in patients with glioblastoma (GBM) and recent work suggests pTau may be a potential a link between neurodegenerative changes and glioblastoma.Using live adult human cortical tissue

…In addition, it has been reported that Tau, a regulat

Alzheimer's disease (AD) is characterized by an early hippocampus hyperactivity triggered by Aβ oligomers (Aβo) in humans and AD mouse models, followed by hypoactivity and synaptic loss occurring before cognitive decline. GWAS identified PTK2B gene encoding for Pyk2, a tyrosine kinase involved in synaptic plasticity, as a new AD risk factor. Several studies have validated Pyk2 involvement in AD pathophysiology, but its exact role is still debated due to conflicting results. The objective of this project is to decipher the role of Pyk2 in synaptic dysfunctions observed in this disease. We first

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

…other proteins such as Amyloid β (Aβ), Tau, and TAR-DNA-binding protein. However, the nature of this association is poorly understood. To investigate the complex pathology of LBD, we constructed 2 novel transgenic overexpressing C. elegans models using human genes (α-synA53T;Taupro-agg and α-synA53T;Aβ1-42;Taupro-agg ). We then investigated the molecular, physiologic, and behavioral alterations of these and previously produced models.

…the Alzheimer’s-associated protein Tau. This co-aggregation correlates with faster disease progression and more severe Parkinson’s symptoms.Microglia are the resident innate immune cells of the brain. They are the first line of immune defense and responsible for the removal of cytotoxic protein aggregates

Obesity is linked to neurodegenerative diseases through neuroinflammation. Pleiotrophin (PTN) is a cytokine that is upregulated in different neuroinflammatory disorders of diverse origin. PTN is a ligand and an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. To investigate the role of RPTP β/ζ, in neuroinflammation and neurodegeneration, we used the APP/PS1 genetic model of Alzheimer disease (AD) and a high-fat diet (HFD)-induced obesity model. Three-month-old wild type (WT) mice were fed with standard chow or HFD (60 Kcal % fat) for three months. MY10, an exogenous R

The interaction of amyloid-beta and microtubule-associated protein tau, the two hallmark proteins of Alzheimer’s disease (AD) age-related pathology, that cause disruption of synaptic long-term potentiation and depression (LTP and LTD, respectively) is still poorly understood. Here, we recorded field excitatory postsynaptic potentials from the CA1 stratum radiatum in young and middle-aged rats under urethane anesthesia to examine the disruptive action of synaptotoxic tau in recombinant protein preparations or aqueous brain extracts from patients with AD and Pick’s disease (PiD) tauopathy. A sin

α-Synuclein (α-Syn) and Tau proteins are neuropathological 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

…beta (AB) deposition and intracellular tau burden. Functional connectivity (FC), the correlation of neuronal signalling between different brain regions, is often impaired in neurological diseases, including AD. Our research focused on investigating the impact of AB pathology on FC using a murine model. We utilized the APP-NLGF (APPKI3) mice as our AD model and compared them with APP-NL (APPKI1) mice as controls. We examined FC changes at two time points: 3

Early dysfunction in Alzheimer's disease (AD) is characterized by abnormal synapse structure and function. We investigated the role of the class II member HDAC4, which controls synaptic plasticity and memory, as potential new modulator of synaptic function in AD. HDAC4 localization and function was assessed in hippocampal tissue from adult control (WT) and 3×Tg mice (AD) by confocal analyses, co-IP and biochemical fractioning. The effects of the overexpression of a cytoplasmic mutant form of HDAC4 (HDACSD) or the empty vector were analyzed in cultured hippocampal neurons or organotypic brain s

Tau, a microtubule-associated protein pivotal for neuronal integrity, is actively involved in retinal development, regulating growth, differentiation, and maturation processes. Mutations in tau can lead to misfolded protein and fibrils formation, disrupting cellular processes and damaging retinal tissue. Previous studies have identified pathological hallmarks of tauopathies, such as Frontotemporal Dementia (FTD), in the retina of patients even in the early stage of pathology. However, the precise molecular mechanisms and the direct sequence of events underlying this process remain poorly under

…(FTLD) proteinopathies: FTLD with tau (FTLD-tau), FTLD with TAR DNA-binding protein 43 (FTLD-TDP) and FTLD with Fused in

Intraneuronal accumulation of the microtubule associated protein Tau is largely recognized as an important toxic factor linked to neuronal 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

…misfolded proteins, namely amyloid and tau, however it is synapse loss which leads to the cognitive impairments associated with the disease. Many studies have focussed on single time points to determine the effects of pathology on synapses however this does not inform on the plasticity of the synapses, that is how they behave in vivo as the pathology progresses. Here we used in vivo two-photon microscopy to assess the temporal dynamics of axonal boutons and dendritic spines in mouse models of tauopathy[1] (rTg4510) and amyloidopathy[2

…pathological proteins amyloid beta and tau contribute to synapse degeneration, and that lowering levels of these proteins can prevent and reverse phenotypes in model systems. Further, she has pioneered high-reso

This seminar is part of our “Emergent Scientists” series, an initiative that provides a platform for scientists at the critical PhD/postdoc transition period to share their work with a broad audience and network. Summary: These talks cover Alzheimer’s disease (AD) research in both mice and humans. Christiana will discuss in particular the translational aspects of applying mouse work to humans and the importance of timing in disease pathology and intervention (e.g. timing between AD biomarkers vs. symptom onset, timing of therapy, etc.). Siddharth will discuss a rare variant of Alzheimer’s dise