Wendy Noble

King's College London | KCL · Department of Basic and Clinical Neuroscience

Molecular chaperones are protective in neurodegenerative diseases by preventing protein misfolding and aggregation, such as extracellular amyloid plaques and intracellular tau neurofibrillary tangles in Alzheimer’s disease (AD). In addition, AD is characterized by an increase in astrocyte reactivity. The chaperone HSPB1 has been proposed as a marke...

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically linked major neurodegenerative diseases. Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene encoding TDP43 cause familial FTD/ALS. There are no cures for FTD/ALS. FTD/ALS display damage to a broad...

Background Highly phosphorylated tau aggregates are deposited in tauopathy brain as disease progresses, driven by a prion‐like spread of tau seeds. Evidence suggests that astrocytes may influence tau spread. However, the efficiency of uptake of disease‐associated tau species is not well defined, nor are the effects of tau uptake on astrocyte reacti...

The purinoceptor P2X7R is a promising therapeutic target for tauopathies, including Alzheimer’s disease (AD). Pharmacological inhibition or genetic knockdown of P2X7R ameliorates cognitive deficits and reduces pathological tau burden in mice that model aspects of tauopathy, including mice expressing mutant human frontotemporal dementia (FTD)-causin...

Astrocytes associate with amyloid plaques in Alzheimer's disease (AD). Astrocytes react to changes in the brain environment, including increasing concentrations of amyloid-β (Aβ). However, the precise response of astrocytes to soluble small Aβ oligomers at concentrations similar to those present in the human brain has not been addressed. In this st...

Astrocytes associate with amyloid plaques in Alzheimer's disease (AD). Astrocytes react to changes in the brain environment, including to increasing concentrations of amyloid-beta (A beta).However, the precise response of astrocytes to soluble small Abeta oligomers at concentrations similar to those present in the human brain has not been addressed...

Synaptic dysfunction is an early pathological feature of neurodegenerative disease and is a close correlate of cognitive decline. Modified tau mislocalises to the synaptic compartment in disease, where some forms of tau interact with synaptic proteins and disrupt synapse function. This study seeks to further explore synaptic tau accumulation, and t...

Highly phosphorylated tau aggregates emerge in affected areas of human tauopathy brain as disease progresses as a result of prion‐like spread and/or replication of seeds. Evidence suggests that astrocytes may influence tau spread. However, the efficiency of uptake of disease‐associated tau species is not well defined, nor are the effects of tau upt...

Alzheimer’s disease (AD) is pathologically characterised by the presence of amyloid plaques and neurofibrillary tangles accompanied by a marked neuroinflammation which contributes to the onset and progression of AD. Astrocytes and microglia recognize danger‐associated molecular patterns (Aß, ATP) through a myriad of sensors including the purinergic...

Background Dysfunctions in the autophagy and endolysosomal pathways have been reported in Alzheimer’s Disease and related tauopathies. The presence of disease‐associated tau itself may play a role in damaging these pathways leading to its altered clearance. Minimal expression of a disease‐associated truncated tau species (Tau35) in mice results in...

Astrocytes are key homeostatic and defensive cells of the central nervous system (CNS). They undertake numerous functions during development and in adulthood to support and protect the brain through finely regulated communication with other cellular elements of the nervous tissue. In Alzheimer's disease (AD), astrocytes undergo heterogeneous morpho...

Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of fundamental physiological processes. This signaling involves close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ″tethering” proteins. The VAPB-PTPIP51 tethers facilitate inositol 1,4,5-trisphosphate (IP3) receptor delivery o...

Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many neuronal functions that are perturbed in amyotrophic lateral sclerosis (ALS) and perturbation to ER-mitochondria signaling is seen in cell and transgenic models of ALS. However, there is currently little evidence that ER-mitochondria signaling is altered in human ALS....

In Alzheimer’s disease, synapse loss causes memory and cognitive impairment. However, the mechanisms underlying synaptic degeneration in Alzheimer’s disease are not well understood. In the hippocampus alterations in the level of cysteine string protein alpha, a molecular co-chaperone at the pre-synaptic terminal, occur prior to reductions in synapt...

Objectives: It has long been considered that accumulation of pathological alpha-synuclein (aSyn) leads to synaptic/neuronal loss which then results in behavioural and cognitive dysfunction. To investigate this claim, we investigated effects downstream of aSyn preformed fibrils (PFF) and 6-hydroxydopamine (6-OHDA), because aSyn PFFs induce spreadin...

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two major neurodegenerative diseases. FTD is the second most common cause of dementia and ALS is the most common form of motor neuron disease. These diseases are now known to be linked. There are no cures or effective treatments for FTD or ALS and so new targets for therapeut...

The autophagy-lysosomal pathway plays a critical role in the clearance of tau protein aggregates that deposit in the brain in tauopathies, including Alzheimer’s disease and defects in this system are associated with disease pathogenesis. Here, we report that expression of Tau35, a tauopathy-associated carboxy-terminal fragment of tau, reduces becli...

Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic...

Background Pathological interactions between β-amyloid (Aβ) and tau drive synapse loss and cognitive decline in Alzheimer’s disease (AD). Reactive astrocytes, displaying altered functions, are also a prominent feature of AD brain. This large and heterogeneous population of cells are increasingly recognised as contributing to early phases of disease...

Background Astrocytes are vital in the onset and progression of Alzheimer’s disease (AD). Accumulation of reactive astrocytes, together with tau phosphorylation, correlates very strongly with cognitive decline. Molecular chaperones are essential for maintaining protein homeostasis. One family of chaperones are the small heat shock proteins (sHSPs),...

Background Deficits in synaptic function and neurite connectivity are early correlates of tauopathies. Altered tau processing and mis‐localization coincide with reductions in synapse density and synaptic function, suggesting a causal role for tau in disease pathogenesis. In parallel, altered activity of hyperpolarization‐activated cyclic nucleotide...

Background Intracellular accumulation of insoluble tau is an important hallmark of Alzheimer’s disease (AD) and related tauopathies. We have previously identified in human tauopathy brain a truncated tau species (Tau35), comprising the C‐terminal half with four microtubule‐binding repeats. Minimal Tau35 expression in transgenic mice results in a pr...

Background: Neuroinflammation is thought to contribute to the onset and/or progression of Alzheimer´s disease (AD). Astrocytes and microglia sense danger-associated molecules (e.g. Aβ species, ATP) through membrane receptors including the purinergic receptor P2X7 (P2X7R). These interactions activate pro-inflammatory pathways and lead to the releas...

Intracellular accumulation of insoluble tau is an important hallmark of Alzheimer’s disease (AD) and related tauopathies. We have previously identified in human tauopathy brain a truncated tau species (Tau35), comprising the C‐terminal half with four microtubule‐binding repeats. Minimal Tau35 expression in transgenic mice results in a progressive t...

Background: Highly phosphorylated tau aggregates spread in a prion-like manner through tauopathy brain. Increasing evidence suggests that astrocytes may influence tau spread, with recent data describing mechanisms of tau uptake my astrocytes. However, the efficiency of uptake of different disease-associated tau species is not well defined, nor is...

Background Pathological interactions between β-amyloid (Aβ) and tau drive the synapse loss that underlies neural circuit disruption and cognitive decline in Alzheimer’s disease (AD). Reactive astrocytes, displaying altered functions, are also a prominent feature of AD brain. This large and heterogeneous population of cells are increasingly recognis...

The enteric nervous system plays a critical role in the regulation of gastrointestinal tract functions and is often referred to as the ‘second brain’ because it shares many features with the central nervous system. These similarities include among others a large panel of neurotransmitters, a large population of glial cells and a susceptibility to n...

Neurodegenerative tauopathies are characterized by deposition in the brain of highly phosphorylated and truncated forms of tau, but how these impact on cellular processes remains unknown. Here, we show that hyperpolarization-induced membrane voltage ‘sag’, which is dependent on hyperpolarization-activated inward-rectifying (I h ) current and hyperp...

Background Glial function is altered in Alzheimer’s disease (AD) in response to danger‐associated molecular patterns in the local environment such as the binding of Aβ species to toll‐like and purinergic receptors, including P2X7R. These interactions activate pro‐inflammatory pathways and lead to the release of cytokines and chemokines that partici...

Background Previous results from our group showed that abeta‐stimulated astrocytes release factors that are detrimental to neurons. Our aim is to investigate and validate those factors. One cytokine in particular is shown to be increased after treatment with low concentrations of oligomeric abeta and has been associated with abnormal tau cleavage....

Among Alzheimer's disease (AD) brain hallmarks, the presence of reactive astrocytes was demonstrated to correlate with neuronal loss and cognitive deficits. Evidence indeed supports the role of reactive astrocytes as mediators of changes in neurons, including synapses. However, the complexity and the outcomes of astrocyte reactivity are far from be...

Tauopathies are a group of neurodegenerative diseases characterized by the progressive accumulation across the brain of hyperphosphorylated aggregates of the microtubule-associated protein tau that vary in isoform composition, structural conformation and localization. Tau aggregates are most commonly deposited within neurons but can show differenti...

An accumulating body of literature has emerged in the past 25 years to show that Parkinson’s disease (PD) is not only a disorder of the brain but also of the gastrointestinal tract and more generally of the gut-brain axis. Gastrointestinal symptoms occur in almost every PD patient at some point and in nearly every case examined pathologically autop...

Background: Among Alzheimer’s disease (AD) brain hallmarks, the presence of reactive astrocytes was demonstrated to correlate with neuronal loss and cognitive deficits. Evidence indeed supports the role of reactive astrocytes as mediators of changes in neurons, including synapses. However, the complexity and the outcomes of astrocyte reactivity are...

Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions, many of which are perturbed in Alzheimer's disease. Moreover, damage to ER-mitochondria signaling is seen in cell and transgenic models of Alzheimer's disease. However, as yet there is little evidence that ER-mitochondria signaling is alt...

A sizeable body of evidence has recently emerged to suggest that gastrointestinal (GI) inflammation might be involved in the development of Parkinson's disease (PD). There is now strong epidemiological and genetical evidence linking PD to inflammatory bowel diseases and we recently demonstrated that the neuronal protein alpha-synuclein, which is cr...

Background Minocycline is an anti-inflammatory drug and protects against the toxic effects of β-amyloid in vitro and in animal models of Alzheimer’s disease. To the best of our knowledge, no randomised placebo-controlled clinical trials in patients with Alzheimer’s disease looking at the efficacy and tolerability of minocycline have been carried ou...

A sizeable body of evidence has recently emerged to suggest that gastrointestinal inflammation might be involved in the development of Parkinson's disease. There is now strong epidemiological and genetical evidence linking Parkinson's disease to inflammatory bowel diseases and we recently demonstrated that the neuronal protein alpha-synuclein, whic...

Polymorphisms associated with BIN1 (bridging integrator 1) confer the second greatest risk for developing late onset Alzheimer’s disease. The biological consequences of this genetic variation are not fully understood, however BIN1 is a binding partner for tau. Tau is normally a highly soluble cytoplasmic protein, but in Alzheimer’s disease tau is a...

Damage to axonal transport is an early pathogenic event in Alzheimer's disease. The amyloid precursor protein (APP) is a key axonal transport cargo since disruption to APP transport promotes amyloidogenic processing of APP. Moreover, altered APP processing itself disrupts axonal transport. The mechanisms that regulate axonal transport of APP are th...

Importance There are no disease-modifying treatments for Alzheimer disease (AD), the most common cause of dementia. Minocycline is anti-inflammatory, protects against the toxic effects of β-amyloid in vitro and in animal models of AD, and is a credible repurposed treatment candidate. Objective To determine whether 24 months of minocycline treatmen...

Since the G8 dementia summit in 2013, a number of initiatives have been established with the aim of facilitating the discovery of a disease-modifying treatment for dementia by 2025. This report is a summary of the findings and recommendations of a meeting titled “Tackling gaps in developing life-changing treatments for dementia”, hosted by Alzheime...

Background: Post-translational modifications of tau modify its interaction with binding partners and cause tau mislocalisation and altered tau function in Alzheimer's disease (AD). The AD risk gene BIN1, is a binding partner for tau, however the mechanism by which BIN1 influences tau function is not fully understood. We hypothesised that BIN1 modul...

Cyclin dependent kinase-5 (cdk5)/p35 is a neuronal kinase that regulates key axonal and synaptic functions but the mechanisms by which it is transported to these locations are unknown. Lemur tyrosine kinase-2 (LMTK2) is a binding partner for p35 and here we show that LMTK2 also interacts with kinesin-1 light chains (KLC1/2). Binding to KLC1/2 invol...

Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions. This signaling involves close physical contacts between the two organelles that are mediated by “tethering proteins” that function to recruit regions of ER to the mitochondrial surface. The ER protein, vesicle-associated membrane protein-...

Sleep disruption promotes the spread of damaging tau pathology in Alzheimer's disease

Human tauopathies including Alzheimer’s disease, progressive supranuclear palsy and related disorders, are characterized by deposition of pathological forms of tau, synaptic dysfunction and neuronal loss. We have previously identified a pathogenic C-terminal tau fragment (Tau35) that is associated with human tauopathy. However, it is not known how...

The microtubule-associated protein tau has been identified in several intraneuronal compartments, including in association with synapses. In Alzheimer’s disease, frontotemporal dementia and related tauopathies, highly phosphorylated tau accumulates as intraneuronal protein aggregates that are likely responsible for the demise of neurons and the sub...

Tau is normally a highly soluble phosphoprotein found predominantly in neurons. Six different isoforms of tau are expressed in the adult human CNS. Under pathological conditions, phosphorylated tau aggregates are a defining feature of neurodegenerative disorders called tauopathies. Recent findings have suggested a potential role of the gut-brain ax...

Alzheimer's disease, the most common cause of dementia, is a progressive neurodegenerative disorder characterised by amyloid-beta deposits in extracellular plaques, intracellular neurofibrillary tangles of aggregated tau, synaptic dysfunction and neuronal death. Transgenic rodent models to study Alzheimer’s mimic features of human disease such as a...

The hippocampus has a critical role in cognition and human memory and is one of the most studied structures in the brain. Despite more than 400 years of research, little is known about the Ammon’s horn region cornu ammonis 2 (CA2) subfield in comparison to other subfield regions (CA1, CA3, and CA4). Recent findings have shown that CA2 plays a bigge...

Alzheimer's disease, the most common cause of dementia, is a progressive neurodegenerative disorder characterised by amyloid-beta deposits in extracellular plaques, intracellular neurofibrillary tangles of aggregated tau, synaptic dysfunction and neuronal death. There are no cures for AD and current medications only alleviate some disease symptoms....

Primary data for molecular changes in the slice culture model in comparison to findings made using tissue from aged 3xTg-AD mice

In Alzheimer's disease (AD) and related tauopathies, the microtubule-associated protein tau is highly phosphorylated and aggregates to form neurofibrillary tangles that are characteristic of these neurodegenerative diseases. Our previous work has demonstrated that the thousand-and-one amino acid kinases (TAOKs) 1 and 2 phosphorylate tau on more tha...

Organotypic brain slice culture models provide an alternative to early stage in vivo studies as an integrated tissue system that can recapitulate key disease features, thereby providing an excellent platform for drug screening. We recently described a novel organotypic 3xTg-AD mouse brain slice culture model with key Alzheimer’s disease-like change...

α-Synuclein is strongly linked to Parkinson’s disease but the molecular targets for its toxicity are not fully clear. However, many neuronal functions damaged in Parkinson’s disease are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling involves close physical associations between the two organelles tha...

Tau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates is accompanied by synaptic dysfunction and neural cell death in a range of neurodegenerative disorders, collectively referred to as tauopathies. Recent advances in our understanding of th...

The spatiotemporal transmission of pathological tau in the brain is characteristic of Alzheimer's disease. Release of both soluble and abnormal tau species from healthy neurons is increased upon stimulation of neuronal activity. It is not yet understood whether the mechanisms controlling soluble tau release from healthy neurons is the same as those...

Author summary As our population ages the incidence of neurodegenerative diseases, including Alzheimer’s disease (AD), is predicted to increase dramatically. Despite providing important symptomatic relief, existing treatments for such conditions do not slow-down disease progression, and this will cause an overwhelming future burden on our healthcar...

Lithium dose-dependently activates cncC target genes, but its protection against Aβ42 toxicity is not cncC-dependent. (A) Venn diagrams showing overlap of GO categories differentially altered by lithium treatment of Aβ42 flies (+RU, +Li vs +RU) compared to cncC activation [38], most of which were up- or down-regulated in both conditions. Significan...

Aβ oligomer effects on Nrf2 and Keap1 protein levels. (A) Representative confocal images of Nrf2 (red), Keap1 (green) and DAPI (blue) immunostaining in Aβ oligomer (7PA2CM) vs wtCM-treated SH-SY5Y cells (see methods). Scale bar = 50 μM. (B) Fluorescence intensity measurements of DAPI, Nrf2 and Keap1 staining across profile lines, indicated by arrow...

Dual degradation model of Nrf2 regulation. Under basal conditions (A) Keap1 binds to, and sequesters, Nrf-2 in the cytoplasm and actively targets it for ubiquitination by a Cullin3-based E3 ligase complex, thus enabling its degradation by the proteasome[1]. During conditions of oxidative or xenobiotic damage (B), Keap1 is inhibited by reactive oxid...

Keap1 loss of function effects on WT Aβ42-induced negative geotaxis. Heterozygous loss of Keap1 ameliorated climbing deficiency in flies expressing high levels of WT Aβ42 [37]. P<0.05 comparing +RU, Keap1 del or +RU Keap1 EY5 flies to +RU alone (two-way ANOVA and Tukey’s post-hoc comparison). N = 45–60 flies per condition analysed as 3–4 biological...

Proteasome inhibitor effects on loss of Keap1-induced Aβ42 degradation. (A) Proteasome activity was measured using the fluorogenic peptide substrate LLVY-AMC (see methods). Enhanced activity in response to heterozygous Keap1del mutation (* p<0.05 comparing +RU to +RU, Keap1del) was reduced to basal levels in ArcAβ42-expressing flies following treat...

Compound dose-response curves for Nrf2 activation. Nrf2 activity, as measured by induction of the target gene NQO1 (see methods), in response to compound treatment in WT SH-SY5Y cells. Full dose-response curves are depicted for (A) the Nrf2 activator CDDO-Me, (B) the Keap1-Nrf2 disruptor 22h and (C) the GSK-3 inhibitor TDZD-8. TDZD-8 was a poor act...

Aβ42 inhibits expression of cncC target genes in heads, but not bodies. (A) cncC activity was measured in 14-day-old Arc Aβ42-expressing fly heads and bodies. ** p<0.01 comparing +RU to–RU in heads. For bodies only, no significant effect of ArcAβ42 on gstD1(ARE)–GFP reporter expression was observed compared to controls (p>0.05 comparing +RU to–RU c...

Nrf2/cncC activity in response to disease-related proteotoxic proteins. (A) Western blot analysis of gstD1(ARE)–GFP reporter expression in w1118 controls and flies over-expressing human 0N3R tau or C9orf72 (GR)100 DPRs in adult neurons. Flies were treated with or without 200 μM RU486 for 14 days. (B) Quantitation of WB depicted in (A) above. A sepa...

Mitochondria form close physical associations with the endoplasmic reticulum (ER) that regulate a number of physiological functions. One mechanism by which regions of ER are recruited to mitochondria involves binding of the ER protein VAPB to the mitochondrial protein PTPIP51, which act as scaffolds to tether the two organelles. Here, we show that...

View largeDownload slide CYFIP2 is thought to regulate mRNA translation at synapses. Tiwari et al . reveal reduced CYFIP2 expression in post-mortem Alzheimer’s disease brains, and show that CYFIP2 reduction in mice causes abnormal amyloid production, tau hyperphosphorylation, and spatial memory loss. CYFIP2 could represent a molecular ‘hub’ with p...

Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is f...

View largeDownload slide Post-translational modification of tau is common in human tauopathies. Bondulich et al. generate transgenic mice expressing low levels of a truncated form of tau (Tau35) that is associated with human tauopathy. Tau35 mice develop progressive tau neuropathology and cognitive impairment, modelling human disease. The approved...

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by neuropathological deposits of amyloid plaques and neurofibrillary tangles comprised of β-amyloid and tau protein, respectively. In AD, tau becomes abnormally phosphorylated and aggregates to form intracellular deposits. However, the mechanisms by which tau exerts...

Alterations in calcium homeostasis are widely reported to contribute to synaptic degeneration and neuronal loss in Alzheimer’s disease. Elevated cytosolic calcium concentrations lead to activation of the calcium-sensitive cysteine protease, calpain, which has a number of substrates known to be abnormally regulated in disease. Analysis of human brai...