Tau pathology

…brain analysis showed lower levels of Tau pathology relative to typical PSEN1 E280A carriers. Whole-genome sequencing revealed homozygosity for an Apolipoprotein E mutation (Christchurch, APOECh). As the ApoECh mutation is found within the heparan sulfate proteoglycan (HSPG) binding domain, we hypothes

…studies in a transgenic mouse model of tauopathy found that the elimination of senescent cells led to an improvement in neurodegeneration and cognitive decline. In this project, we aim to unravel the relationship between brain senescence and the onset and pro

Unlike familiar Alzheimer’s Disease (FAD) which is caused by mutations, most common sporadic disease (SAD) arises from a combination of risk factors including inflammation. This study aimed to explore and compare the effects of two pro-inflammatory agents: Western-diet (WD) and Lipopolysaccharide (LPS) of Gram-negative bacteria on initiation of AD molecular markers in the brain in the absence of AD mutations. To this aim, 3 months-old (mo) male C57BL/6J mice were divided into 3 groups: fed with WD, with Standard Diet (SD-CTR) and SD-fed mice injected 3 times with LPS (0.5mg/kg) at 3 mo. Mice w

Histone deacetylase (HDAC) family proteins play important roles in pathological alterations of Alzheimer’s disease (AD). There has been keen interest in developing small molecule inhibitors of HDACs as potential therapeutics of AD. Presently, little is known about the role of HDAC11 in AD and whether HDAC11 can be a potential drug target for AD. Recently, we discovered PB94 as our lead small molecule inhibitor of HDAC11 exhibiting strong potency and selectivity against HDAC11 over other HDAC isoforms, which warranted further optimization and investigation for AD. Here, we optimized PB94 and an

Alzheimer’s disease (AD) is a complex disorder and multiple molecular mechanisms are involved in AD onset and progression. Recent evidences have suggested that metabolic alterations are an important pathological feature in AD. Likewise, diabetes and obesity, two metabolic illnesses, are risk factors for AD. These two diseases are associated with an expansion of visceral adipose tissue (VAT). Here, we hypothesize that the visceral adipose tissue may serve as a key communicator organ between the brain and peripheral metabolic disorders and affecting both types of disorders.We used histological s

Alzheimer’s disease (AD) is marked by amyloid beta accumulation, tau pathology, and cognitive decline. Sleep disturbances in AD are linked to amyloid beta, yet the influence of tau pathology on sleep remains unexplored. Using Drosophila melanogaster, we investigated adult-onset tau expression effects on sleep, addressing the knowledge gap in tauopathy's impact on sleep-related changes in AD progression. Pan-neuronal expression of wild-type tau and pseudo-phosphorylated tau E14 in Drosophila was induced in adult flies by RU 486 and activity and sleep were monitored in an automated Drosophila Ac

…(Aβ) plaques and hyperphosphorylated Tau tangles. Evidence from epidemiology and neuroimaging studies suggest that Type 2 Diabetes (T2DM) and Alzheimer's disease (AD) have a shared pathogenesis. Moreover, insulin resistance has been shown to impact hyperphosphorylation and aggregation of Tau making this an important risk factor for the detection of early

…et al., 2018) and is susceptible to tau pathology and neuronal loss in AD patients. Accordingly, eye movement abnormalities associated with AD are often observed durin

Some individuals with Alzheimer’s disease (AD) pathology exhibit cognitive resilience, offering promising prospects for identifying new therapeutic targets.Aims: Our hypothesis centers around the contribution of resilience to changes in excitatory synapses at the structural and molecular levels, which may underlie healthy cognitive performance in aged AD animals.Methods: We used Morris Water Maze tests, ELISA, western blots, stereological methods and immunoelectron microscopy.Results: Utilizing the Morris Water Maze test, we selected resilient (asymptomatic) and cognitively impaired aged-Tg257

…donors and individuals with differing tau and amyloid burden. Using single-nucl

SUMOylation is a covalent and reversible attachment of an 11 kDa SUMO (Small Ubiquitin-like MOdifier) protein to a lysine residue. SUMOylation act as a biochemical switch to regulate the function of hundreds of proteins in different pathways. In the brain of vertebrates, three main SUMO isoforms (SUMO1-3) are characterized. While SUMO2 and SUMO3 differ by only three N-terminal amino acids, they only share ~50% of their sequences with SUMO1. Global levels of SUMOylated proteins are altered in several neurodegenerative diseases; however, no data are currently available in Fronto-temporal dementi

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

The development of human induced pluripotent stem cells (iPSC) and their subsequent differentiation into neurons has provided new opportunities for the generation of physiologically-relevant, in vitro disease models. I will present our work using iPSC to modal familial Alzheimer's Disease (fAD) and Frontotemporal Dementia (FTD). We have investigated the mutation-specific effects of APP and PSEN1 mutations on Abeta generation in neurons generated from individuals with fAD, revealing distinct mechanisms that may contribute to clinical heterogeneity in disease. I will also discuss our work to und

Glymphatic perivascular exchange is supported by the astroglial water channel aquaporin-4 (AQP4), which localizes to perivascular astrocytic endfeet surrounding the cerebral vasculature. In aging mice, impairment of glymphatic function is associated with reduced perivascular AQP4 localization, yet whether these changes contribute to the development of neurodegenerative disease, such as Alzheimer’s disease (AD), remains unknown. Using post mortem human tissue, we evaluated perivascular AQP4 localization in the frontal cortical gray matter, white matter, and hippocampus of cognitively normal sub

…AD with Aβ accumulation upstream and Tau pathology, inflammation, synaptic dysfunction, neuronal loss and dementia downstream, all interlinked, initiated and driven by Aβ42 peptides or oligomers. The genetic mutations causing familial Alzheimer disease seem to support this model. The nagging problem remains however that the postulated causal, and especially the ’driving’ role of abnormal Aβ aggr