The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics

Hardy, John; Selkoe, Dennis J.

doi:10.1126/science.1072994

Cited by 12,395 publications

(9,817 citation statements)

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“…Aggregation and deposition of β‐amyloid (Aβ) and the formation of neurofibrillary tangles are classical hallmarks of AD (Hardy and Selkoe, 2002). Aβ deposition in the brain seems to precede neurofibrillary tangle formation, neuronal cell death and subsequent functional decline (Jack et al, 2010).…”

Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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“…Alzheimer's disease (AD) -the most common form of age-related dementia -is a progressive neurodegenerative disorder characterized by a deficit in cognitive processes that are manifested as alterations in memory, judgment and reasoning (reviewed in Hardy and Selkoe, 2002). To date, several studies have shown that the Wnt signaling components b-catenin and GSK3b form multiprotein complexes with the early-onset familial AD-linked presenilin proteins (Zhou et al, 1997;Takashima et al, 1998b;Kang et al, 2002).…”

Section: Alzheimer's Disease Apolipoprotein E and Wnt Signalingmentioning

confidence: 99%

The ups and downs of Wnt signaling in prevalent neurological disorders

2006

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In order to function properly, the brain must be wired correctly during critical periods in early development. Mistakes in this process are hypothesized to occur in disorders like autism and schizophrenia. Later in life, signaling pathways are essential in maintaining proper communication between neuronal and non-neuronal cells, and disrupting this balance may result in disorders like Alzheimer's disease. The Wnt/b-catenin pathway has a well-established role in cancer. Here, we review recent evidence showing the involvement of Wnt/b-catenin signaling in neurodevelopment as well as in neurodegenerative diseases. We suggest that the onset/development of such pathological conditions may involve the additive effect of genetic variation within Wnt signaling components and of molecules that modulate the activity of this signaling cascade.

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“…The accumulation of amyloid‐β (Aβ) plaques in the brain is one of the first events in the pathological cascade leading to Alzheimer's disease (AD) (Bateman et al., 2012; Hardy & Selkoe, 2002; Sperling et al., 2010). Aβ disrupts synaptic functioning, resulting in aberrant brain connectivity at the synaptic level (Selkoe, 2002; Spires‐Jones & Hyman, 2014), as well as on the whole‐brain connectivity level (Delbeuck, der Linden, & Collette, 2003; Hedden et al., 2009).…”

Section: Introductionmentioning

confidence: 99%

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

et al. 2018

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IntroductionAmyloid plaque deposition in the brain is an early pathological change in Alzheimer's disease (AD), causing disrupted synaptic connections. Brain network disruptions in AD have been demonstrated with eigenvector centrality (EC), a measure that identifies central regions within networks. Carrying an apolipoprotein (APOE)‐ε4 allele is a genetic risk for AD, associated with increased amyloid deposition. We studied whether APOE‐ε4 carriership is associated with EC disruptions in cognitively normal individuals.MethodsA total of 261 healthy middle‐aged to older adults (mean age 56.6 years) were divided into high‐risk (APOE‐ε4 carriers) and low‐risk (noncarriers) groups. EC was computed from resting‐state functional MRI data. Clusters of between‐group differences were assessed with a permutation‐based method. Correlations between cluster mean EC with brain volume, CSF biomarkers, and psychological test scores were assessed.ResultsDecreased EC in the visual cortex was associated with APOE‐ε4 carriership, a genetic risk factor for AD. EC differences were correlated with age, CSF amyloid levels, and scores on the trail‐making and 15‐object recognition tests.ConclusionOur findings suggest that the APOE‐ε4 genotype affects brain connectivity in regions previously found to be abnormal in AD as a sign of very early disease‐related pathology. These differences were too subtle in healthy elderly to use EC for single‐subject prediction of APOE genotype.

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The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics

Cited by 12,395 publications

References 88 publications

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

The ups and downs of Wnt signaling in prevalent neurological disorders

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

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