Neurovascular dysfunction, inflammation and endothelial activation: Implications for the pathogenesis of Alzheimer's disease

Garrison Institute on Aging, and Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
Journal of Neuroinflammation (Impact Factor: 4.9). 03/2011; 8:26. DOI: 10.1186/1742-2094-8-26
Source: PubMed

ABSTRACT Alzheimer's disease (AD) is an age-related disorder characterized by progressive cognitive decline and dementia. Alzheimer's disease is an increasingly prevalent disease with 5.3 million people in the United States currently affected. This number is a 10 percent increase from previous estimates and is projected to sharply increase to 8 million by 2030; it is the sixth-leading cause of death. In the United States the direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $172 billion each year. Despite intense research efforts, effective disease-modifying therapies for this devastating disease remain elusive. At present, the few agents that are FDA-approved for the treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed. Although the idea that vascular defects are present in AD and may be important in disease pathogenesis was suggested over 25 years ago, little work has focused on an active role for cerebrovascular mechanisms in the pathogenesis of AD. Nevertheless, increasing literature supports a vascular-neuronal axis in AD as shared risk factors for both AD and atherosclerotic cardiovascular disease implicate vascular mechanisms in the development and/or progression of AD. Also, chronic inflammation is closely associated with cardiovascular disease, as well as a broad spectrum of neurodegenerative diseases of aging including AD. In this review we summarize data regarding, cardiovascular risk factors and vascular abnormalities, neuro- and vascular-inflammation, and brain endothelial dysfunction in AD. We conclude that the endothelial interface, a highly synthetic bioreactor that produces a large number of soluble factors, is functionally altered in AD and contributes to a noxious CNS milieu by releasing inflammatory and neurotoxic species.

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Available from: Paula Grammas, Aug 28, 2015
    • "Because the brain cannot be isolated from the rest of the organism, these influences reflect changes in the basic molecular, cellular and physiological processes across virtually all organs and systems. Although the precise roster of the factors determining brain aging is yet to be completed, it is clear that fundamental energetic processes within the mitochondria deteriorate with advancing age (Boumezbeur et al. 2010), and that this deterioration is promoted by aggregate action of reactive oxygen species (ROS, Dröge and Schipper 2007), chronic neuroinflammation (Finch and Crimmins 2004; Finch et al. 1969; Grammas 2011), and other contributors to a general age-related increase in frailty (Rockwood et al. 2004). The precursors of age-related frailty stem from manifold biochemical and physiological factors, yet they have at least one thing in common: their association with the action, flow and accumulation of iron. "
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    ABSTRACT: Age-related increase in frailty is accompanied by a fundamental shift in cellular iron homeostasis. By promoting oxidative stress, the intracellular accumulation of non-heme iron outside of binding complexes contributes to chronic inflammation and interferes with normal brain metabolism. In the absence of direct non-invasive biomarkers of brain oxidative stress, iron accumulation estimated in vivo may serve as its proxy indicator. Hence, developing reliable in vivo measurements of brain iron content via magnetic resonance imaging (MRI) is of significant interest in human neuroscience. To date, by estimating brain iron content through various MRI methods, significant age differences and age-related increases in iron content of the basal ganglia have been revealed across multiple samples. Less consistent are the findings that pertain to the relationship between elevated brain iron content and systemic indices of vascular and metabolic dysfunction. Only a handful of cross-sectional investigations have linked high iron content in various brain regions and poor performance on assorted cognitive tests. The even fewer longitudinal studies indicate that iron accumulation may precede shrinkage of the basal ganglia and thus predict poor maintenance of cognitive functions. This rapidly developing field will benefit from introduction of higher-field MRI scanners, improvement in iron-sensitive and -specific acquisition sequences and post-processing analytic and computational methods, as well as accumulation of data from long-term longitudinal investigations. This review describes the potential advantages and promises of MRI-based assessment of brain iron, summarizes recent findings and highlights the limitations of the current methodology.
    Neuropsychology Review 08/2015; DOI:10.1007/s11065-015-9292-y · 5.40 Impact Factor
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    • "Cerebrovascular abnormalities associated to AD can result in hypoperfusion, hypoxia, focal chronic inflammation and compromised function and permeability of brain blood barrier (BBB). These injuries are exacerbated by Aβ peptides deposition, which may initiate neurodegeneration and eventually cognitive decline (Zlokovic, 2005; Grammas, 2011; Kelleher and Soiza, 2013; Li et al., 2015). "
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    ABSTRACT: Alzheimer’s disease (AD) is the most common neurodegenerative cause of dementia in the elderly. AD is accompanied by the accumulation of amyloid peptides in the brain parenchyma and in the cerebral vessels. The sporadic form of AD accounts for about 95% of all cases. It is characterized by a late onset, typically after the age of 65, with a complex and still poorly understood aetiology. Several observations point towards a central role of cerebrovascular dysfunction in the onset of sporadic AD (SAD). According to the “vascular hypothesis”, AD may be initiated by vascular dysfunctions that precede and promote the neurodegenerative process. In accordance to this, AD patients show increased hemorrhagic or ischemic stroke risks. It is now clear that multiple bidirectional connections exist between AD and cerebrovascular disease, and in this new scenario, the effect of amyloid peptides on vascular cells and blood platelets appear to be central to AD. In this review, we analyze the effect of amyloid peptides on vascular function and platelet activation and its contribution to the cerebrovascular pathology associated with AD and the progression of this disease.
    Frontiers in Cellular Neuroscience 03/2015; DOI:10.3389/fncel.2015.00065 · 4.18 Impact Factor
    • "Determining the etiopathogenesis of dementia is a crucial aspect of studies dealing with cognitive functions. There is a consensus among researchers that vascular lesions, oxidative stress, inflammatory processes and abnormal neurotransmission are associated with the development of dementia, including Alzheimer's disease (Grammas 2011). An antioxidative activity of cryotherapy carried out on patients with multiple sclerosis has been shown in several studies. "
    European Psychiatry 03/2015; 30:1454. DOI:10.1016/S0924-9338(15)31127-5 · 3.44 Impact Factor
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