Amyloid-beta

…by extracellular accumulation of amyloid-beta. Estrogen receptors (ERs) are widely recognized as mediators of neuroprotection from various insults. Recent research has highlighted the distinction between nuclear and non-nuclear ER activation mechanisms, positioning non-nuclear ERs as a safer option, devoid of the cardiovascular and cancer risks associated with nuclear ER activation. In this study, we aimed to confirm the neuroprotective potential of PaPE-1, a novel compound that preferentially activates non-nuc

…showed a crosstalk between cNs and amyloid-beta (Aβ), a peptide extensively known for its pathological role in AD but also implicated in the physiological processes of synaptic plasticity and memory.Based on these f

Amyloid-beta (Aβ)-induced changes in neuronal activity could yield valuable early markers of Alzheimer’s disease (AD). The neurophysiological manifestations associated with early Aβ-pathology in humans are however not well defined. This study investigated the relationship between Aβ-pathology and neurophysiological characteristics in 110 cognitively unimpaired individuals (65.9±5.7 years). All subjects underwent 18F-flutemetamol-PET imaging and resting-state magnetoencephalography (MEG) recording at baseline and 4-year follow-up. We tested associations between baseline Aβ-binding potentials (B

…approach to reduce the accumulation of amyloid-beta (Aβ) peptides, a critical event in the onset of the disease. Emerging evidence indicate that metabotropic glutamate receptors (mGluRs) are involved in the progression of AD, representing potential targets for new treatments. Studies have highlighted the potential role of group II mGluRs, mGluR2 and mGluR3, in the modulation of Aβ production, although their respective contribution remains unclear, due to the lack of specific tools to study them. Here, we showed in vitro that enhancing mG

Among the three ApoE isoforms, ApoE4 is a major risk factor for sporadic AD due to its impact on amyloid beta (Abeta) clearance and plaque formation. Although extensive research has connected ApoE to various AD-related pathologies beyond Abeta, its association with ApoE isoforms remains an area that requires further investigation. This study aimed to elucidate the effects of ApoE isoforms on AD pathology using human ApoE Knock-In (KI) AD mouse models. First, we generated an APPNL-G-F;hApoE (ApoE Double KI) mouse model by crossing human ApoE3 or ApoE4 KI mice with APPNL-G-F KI mice. Additionall

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

Therapeutic interventions’ lackluster performance in Alzheimer dementia (AD) may in part be due to the irreversibly advanced stage of the pathological process underlying cognitive decline once the latter is diagnosed. Currently, clinical diagnosis of AD is supported by in vivo molecular imaging of disease-related Aβ and Tau aggregates in the brain, and analysis of cerebrospinal fluid. Positron Emission Tomography, Single Photon Emission Computed Tomography, and Magnetic Resonance imaging are the most common methods used. They are costly, which limits their use in routine screening. We used flu

Pathological amyloid beta (Aβ) accumulation in the brain has been associated with poor cognitive performance and aberrant neuronal activity in preclinical mouse models of Alzheimer’s disease (AD). Here, we assessed the impact of advanced Aβ pathology on spatial information processing in the medial entorhinal cortex (MEC) of 18-month APP NL-G-F knock-in mice as they explored contextually novel and familiar open field arenas in a two-day, four-session recording paradigm. Using in vivo electrophysiology, we tracked single-units across all sessions and found that MEC single-unit spatial informatio

Synaptic dysfunction in response to amyloid-beta (Aß) accumulation is increasingly recognized as a precursor of cognitive decline in Alzheimer's Disease (AD). AMPA receptors (AMPARs), the major neurotransmitter receptors in the brain, are implicated in the synaptic dysfunction observed in rodent models expressing amyloidogenic APP mutations. AMPARs are proposed to undergo aberrant trafficking, characterized by changes in their subunit composition and subcellular localization. The precise mechanisms underlying the dysregulation of AMPAR trafficking in AD remain poorly understood.Here, we apply

The neuroprotective BDNF/TrkB-FL system is compromised in Alzheimer’s disease (AD). Amyloid-beta triggers calpain-mediated TrkB-FL receptor cleavage, leading to TrkB-ICD formation, a novel intracellular toxic fragment. Biological fluids are used to pinpoint potential disease biomarkers and extracellular vesicles (EVs) are cell-specific carriers of promising pathological biomarkers. Thus, this work aimed to investigate the presence of TrkB-ICD in AD human samples and EVs. Protein and RNA was extracted from human AD post-mortem brain samples classified according to the Braak staging (stages 0-II

Alzheimer's disease (AD) develops undiagnosed for years. Diagnosis of AD remains relatively invasive and restricted to specialized centers calling for development of the new diagnostic markers. Retina may be an attractive source of such markers because it is an accessible part of the CNS (in vivo imaging and electrophysiology). Recent studies indicate pathological alterations in retina of AD patients such as retinal ganglion cell degeneration. Recently, we showed a dysfunction in the glutaminergic photoreceptor synapsis associated with a strong expression of phosphorylated tau proteins (p-tau)

Microglia, as macrophages in the brain, exhibit dysfunction with aging, such as impaired phagocytic capability and elevated neuroinflammation. However, the mechanisms underlying microglial aging remain unclear. The heterogeneity of microglia further challenges this context. Disrupted-in-schizophrenia 1 (DISC1), a psychiatric disorder susceptibility gene disrupted by translocation, plays an essential role in regulating the development and function of neurons. We observe that DISC1 is also expressed in microglia, where it exhibits an aggregates-like pattern (Figure A). We called this population

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

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by distinct pathologies, including extracellular amyloid 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

SorCS2 is a mammalian sorting receptor that is induced in astrocytes after stroke to support tissue regeneration (Malik et al., Glia 2020). It has been shown that SNP variants of SORCS2 have epistatic effects on Alzheimer’s disease (AD) risk (Reitz et al., Translational Psychiatry 2013), and that SorCS2 deletion in the AD mouse model causes decline in astrocyte number accompanied by a profound increase in toxic amyloid beta (Ab) levels (Network Glia Conference 2023, #341). These observations suggest that astrocyte-expressed SorCS2 may play a protective role not only after stroke, but also in A

Recent studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aβ deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Disruption of SYK signaling in this

…are associated with early amyloid-beta (Aβ) brain burden, hallmark of AD neuropathology, and cognitive change at 2 years in 100 late-midlife healthy individuals. We first found th

Alzheimer's disease (AD) is the most common cause of dementia, and its health and socioeconomic burdens are of major concern. Presently, a definite diagnosis of AD is established by examining brain tissue after death. These examinations focus on two major pathological hallmarks of AD in the brain: (i) amyloid plaques consisting of aggregated amyloid beta (Aβ) peptides and (ii) neurofibrillary tangles made of abnormally phosphorylated tau protein. In living individuals, AD diagnosis relies on two main approaches: (i) brain imaging of tau tangles and Aβ plaques using a technique called positron

Tara Spires-Jones’ research focuses on the mechanisms and reversibility of neurodegeneration in Alzheimer’s disease, other degenerative brain diseases, and ageing. The objective of her research group is to understand why synapses and neurons become dysfunctional and die in these diseases in order to develop effective therapeutic strategies. Her work has shown that soluble forms of the 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