P3‐060: Soluble Aβ promotes wild‐type tau pathology <i>in vivo</i>

Chabrier, Meredith A.; Blurton‐Jones, Mathew; Agazaryan, Andy; Nerhus, Joy L.; LaFerla, Frank M.; Coria, Hilda Martinez

doi:10.1016/j.jalz.2012.05.1279

Cited by 12 publications

(15 citation statements)

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“…S3): Amyloid may aggregate throughout highly interconnected cortical hub regions in association neocortex, driven by high neural activity (34), along with decreased clearance in predisposed individuals (59), producing high local concentrations of Aβ. Possibly facilitated by Aβ (60), tau pathology may develop in vulnerable networks, such as the posterior DMN, and then spread transneuronally (15)(16)(17) into closely interconnected networks, including those involved in visuospatial, language, and executive function. This may lead to neurodegeneration in specific functional networks, resulting in heterogeneous clinicoanatomical AD phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer’s disease

Lehmann

Madison

Ghosh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

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Although previous studies have emphasized the vulnerability of the default mode network (DMN) in Alzheimer's disease (AD), little is known about the involvement of other functional networks and their relationship to clinical phenotype. To test whether clinicoanatomic heterogeneity in AD is driven by the involvement of specific networks, network connectivity was assessed in healthy subjects by seeding regions commonly and specifically atrophied in three clinical AD variants: early-onset AD (age at onset, <65 y; memory and executive deficits), logopenic variant primary progressive aphasia (language deficits), and posterior cortical atrophy (visuospatial deficits). Four-millimeter seed regions of interest were used to obtain intrinsic connectivity maps in 131 healthy controls (age, 65.5 ± 3.5 y). Atrophy patterns in independent cohorts of AD variant patients and their correspondence to connectivity networks in controls were also assessed. The connectivity maps of commonly atrophied regions of interest support posterior DMN and precuneus network involvement across AD variants, whereas seeding regions specifically atrophied in each AD variant revealed distinct, syndrome-specific connectivity patterns. Goodness-of-fit analysis of each connectivity map with network templates showed the highest correspondence between the early-onset AD seed connectivity map and anterior salience and right executive-control networks, the logopenic aphasia seed connectivity map and the language network, and the posterior cortical atrophy seed connectivity map and the higher visual network. Connectivity maps derived from controls matched regions commonly and specifically atrophied in the patients. Our findings indicate that the posterior DMN and precuneus network are commonly affected in AD variants, whereas syndrome-specific neurodegenerative patterns are driven by the involvement of specific networks outside the DMN. A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by extracellular accumulation of amyloid plaques, intracellular neurofibrillary tangles, and neuronal loss (1). Although most patients present with memory deficits, a significant minority of patients with AD present with nonamnestic syndromes (2, 3). Patients with nonfamilial early-onset AD (EOAD, defined as onset <65 y in most studies) often show heterogeneous cognitive deficits, including impairment in attention and executive functions (4, 5). Focal syndromes such as posterior cortical atrophy (PCA, characterized by predominant visuospatial and visuoperceptual deficits; ref. 6) and the logopenic variant of primary progressive aphasia [lvPPA, a progressive disorder of language (7,8)] are also most commonly caused by AD pathology. It has been suggested that up to 15% of patients with AD seen in dementia centers have nonamnestic presentations (2), and the importance of these syndromes is reflected in their inclusion in new diagnostic guidelines for AD (9, 10). The factors driving the clinicoanatomical heterogeneity in AD are not well understoo...

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Section: Discussionmentioning

confidence: 99%

Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer’s disease

Lehmann

Madison

Ghosh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

View full text Add to dashboard Cite

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“…Moreover, incubation of organotypic hippocampal cultures with Aβ also shows neurodegeneration concomitant with a significant increase in Tau phosphorylation [11]. Chabrier et al have recently shown that soluble Aβ promotes Tau pathology in vivo [12] and moreover, a three-dimensional human neural cell culture from familial Alzheimer disease patients who present mutations that increase Aβ levels shows Aβ plaques followed by aggregates of phosphorylated Tau [13]. However, the mechanisms linking Aβ toxicity and Tau hyperphosphorylation remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms linking amyloid β toxicity and Tau hyperphosphorylation in Alzheimer׳s disease

Lloret

Fuchsberger

Giraldo

et al. 2015

Free Radical Biology and Medicine

114

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“…These specific behavioural and molecular effects were reversed by lithium chloride, a GSK-3β inhibitor (Nery et al, 2014). In a double-transgenic mouse model expressing low levels of Arctic mutant Aβ that mimics the near physiological levels of soluble Aβ found early in AD, soluble Aβ forms facilitate cognitive impairment and profoundly influence the progression of tau pathology (Chabrier et al, 2012). Studies performed on triple transgenic (3×Tg-AD) mice also confirmed that pathological tau forms are found together with the accumulation of Aβ oligomers (McKee et al, 2008).…”

Section: Interplay Between Aβ and Tau Hyperphosphorylation In Admentioning

confidence: 99%

The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer’s disease

Jembrek

Slade

Hof

et al. 2018

Progress in Neurobiology

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Alzheimer's disease (AD), the most common progressive neurodegenerative disorder, is characterized by severe cognitive decline and personality changes as a result of synaptic and neuronal loss. The defining clinicopathological hallmarks of the disease are deposits of amyloid precursor protein (APP)-derived amyloid-β peptides (Aβ) in the brain parenchyma, and intracellular aggregates of truncated and hyperphosphorylated tau protein in neurofibrillary tangles (NFT). At the cellular and molecular levels, many intertwined pathological mechanisms that relate Aβ and tau pathology with a transcription factor p53 have been revealed. p53 is activated in response to various stressors that threaten genomic stability. Depending on damage severity, it promotes neuronal death or survival, predominantly via transcription-dependent mechanisms that affect expression of apoptosis-related target genes. Levels of p53 are enhanced in the AD brain and maintain sustained tau hyperphosphorylation, whereas intracellular Aβ directly contributes to p53 pool and promotes downstream p53 effects. The review summarizes the role of p53 in neuronal function, discusses the interactions of p53, tau, and Aβ in the normal brain and during the progression of AD pathology, and considers the impact of the most prominent hereditary risk factors of AD on p53/tau/Aβ interactions. A better understanding of this intricate interplay would provide deeper insight into AD pathology and might offer some novel therapeutic targets for the improvement of treatment options. In this regard, drugs and natural compounds targeting the p53 pathway are of growing interest in neuroprotection as they may represent promising therapeutic approaches in the prevention of oxidative stress-dependent pathological processes underlying AD.

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P3‐060: Soluble Aβ promotes wild‐type tau pathology in vivo

Cited by 12 publications

References 0 publications

Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer’s disease

Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer’s disease

Molecular mechanisms linking amyloid β toxicity and Tau hyperphosphorylation in Alzheimer׳s disease

The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer’s disease

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