Alzheimer Disease in 2020

Holtzman, David M.; Mandelkow, Eckhard; Selkoe, Dennis J.

doi:10.1101/cshperspect.a011585

Cited by 100 publications

(83 citation statements)

References 3 publications

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“…1). Although the impact of endothelial dysfunction in atherosclerosis and cerebrovascular diseases is well appreciated, recent evidence implicates alterations in endothelial function also in Alzheimer's disease (AD), the major cause of dementia in the elderly (Holtzman et al 2012; Iadecola 2013). It is now well established that the amyloid-β peptide (Aβ), a key pathogenic factor in AD, has powerful cerebrovascular effects that alter the regulation of the cerebral circulation.…”

Section: Introductionmentioning

confidence: 99%

Endothelial Dysfunction and Amyloid-β-Induced Neurovascular Alterations

2015

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Alzheimer's disease (AD) and cerebrovascular diseases share common vascular risk factors that have disastrous effects on cerebrovascular regulation. Endothelial cells, lining inner walls of cerebral blood vessels, form a dynamic interface between the blood and the brain and are critical for the maintenance of neurovascular homeostasis. Accordingly, injury in endothelial cells is regarded as one of the earliest symptoms of impaired vasoregulatory mechanisms. Extracellular buildup of amyloid-β (Aβ) is a central pathogenic factor in AD. Aβ exerts potent detrimental effects on cerebral blood vessels and impairs endothelial structure and function. Recent evidence implicates vascular oxidative stress and activation of the nonselective cationic channel transient receptor potential melastatin (TRPM)-2 on endothelial cells in the mechanisms of Aβ-induced neurovascular dysfunction. Thus, Aβ triggers opening of TRPM2 channels in endothelial cells leading to intracellular Ca2+ overload and vasomotor dysfunction. The cerebrovascular dysfunction may contribute to AD pathogenesis by reducing the cerebral blood supply, leading to increased susceptibility to vascular insufficiency, and by promoting Aβ accumulation. The recent realization that vascular factors contribute to AD pathobiology suggests new targets for the prevention and treatment of this devastating disease.

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Section: Introductionmentioning

confidence: 99%

Endothelial Dysfunction and Amyloid-β-Induced Neurovascular Alterations

2015

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“…The deposition of aggregated Aβ peptide in the brain parenchyma is an early and obligatory event in the pathogenesis of Alzheimer’s disease (AD) [12, 14]. Studies in several laboratories have demonstrated that Aβ aggregation can be instigated in the living brain by exogenous, Aβ-rich brain extracts [8, 9, 11, 17, 19, 20, 21, 28, 30, 34, 35], and that the causative agent is an aggregated form of Aβ itself [16, 20, 30].…”

Section: Introductionmentioning

confidence: 99%

Aβ seeds resist inactivation by formaldehyde

Fritschi

Cintron

et al. 2014

Acta Neuropathol

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Cerebral β-amyloidosis can be exogenously induced by the intracerebral injection of brain extracts containing aggregated β-amyloid (Aβ) into young, pre-depositing Aβ precursor protein- (APP) transgenic mice. Previous work has shown that the induction involves a prion-like seeding mechanism in which the seeding agent is aggregated Aβ itself. Here we report that the β-amyloid-inducing activity of Alzheimer’s disease (AD) brain tissue or aged APP-transgenic mouse brain tissue is preserved, albeit with reduced efficacy, after formaldehyde fixation. Moreover, spectral analysis with amyloid conformation-sensitive luminescent conjugated oligothiophene dyes reveals that the strain-like properties of aggregated Aβ are maintained in fixed tissues. The resistance of Aβ seeds to inactivation and structural modification by formaldehyde underscores their remarkable durability, which in turn may contribute to their persistence and spread within the body. The present findings can be exploited to establish the relationship between the molecular structure of Aβ aggregates and the variable clinical features and disease progression of AD even in archived, formalin-fixed autopsy material.

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“…AD is the most common form of dementia and is characterized at the neuropathological level by the accumulation of extracellular plaques and intraneuronal neurofibrillary tangles that are composed of A␤ peptides and the microtubule-associated protein tau, respectively (52)(53)(54). A␤ derives from the amyloid precursor protein (APP) by sequential proteolytic processing by ␤-and ␥-secretase (55,56).…”

Section: Molecular Genetics Of Alzheimer Diseasementioning

confidence: 99%

The Triggering Receptor Expressed on Myeloid Cells 2: A Molecular Link of Neuroinflammation and Neurodegenerative Diseases

Walter

2016

Journal of Biological Chemistry

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The triggering receptor expressed on myeloid cells (TREM) 2 is a member of the immunoglobulin superfamily of receptors and mediates signaling in immune cells via engagement of its co-receptor DNAX-activating protein of 12 kDa (DAP12). Homozygous mutations in TREM2 or DAP12 cause Nasu-Hakola disease, which is characterized by bone abnormalities and dementia. Recently, a variant of TREM2 has also been associated with an increased risk for Alzheimer disease. The selective expression of TREM2 on immune cells and its association with different forms of dementia indicate a contribution of this receptor in common pathways of neurodegeneration.

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Alzheimer Disease in 2020

Cited by 100 publications

References 3 publications

Endothelial Dysfunction and Amyloid-β-Induced Neurovascular Alterations

Endothelial Dysfunction and Amyloid-β-Induced Neurovascular Alterations

Aβ seeds resist inactivation by formaldehyde

The Triggering Receptor Expressed on Myeloid Cells 2: A Molecular Link of Neuroinflammation and Neurodegenerative Diseases

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