Vascular Dysfunction in the Brain as an Important Cause of Alzheimer's Disease
As we age, the vascular system becomes ever more dysfunctional in a number of ways. The density of capillaries declines, lowering the rate at which nutrients are delivered to energy-hungry tissues. The blood-brain barrier begins to leak, allowing inappropriate molecules and cells into the brain to provoke inflammation. Hypertension produces pressure damage to delicate tissues, and the ongoing rupture of tiny blood vessels, destroying small volumes of tissue. As researchers attempt to understand the relative importance of the many possible contributing causes of neurodegenerative conditions such as Alzheimer's disease, in the wake of the failure of protein aggregate clearance to improve patient outcomes, it is a reasonable argument to suggest that vascular dysfunction provides a meaningful contribution to the age-related decline of the brain.
Alzheimer's disease (AD) is the most common form of neurodegenerative disease in elder population worldwide. AD is clinically characterized as cognitive decline and psychiatric manifestations. The pathological hallmarks of AD brain are the accumulation of extracellular β-amyloid (Aβ) (senile plaques) and the intracellular twisted strands of the hyper-phosphorylated tau protein (neurofibrillary tangles). These changes in the brain are accompanied by the neuronal damage.
AD is a progressive neurodegenerative disorder that can start decades before the appearance of clinical symptoms. Although several pathological mechanisms of AD have been identified, no satisfactorily effective therapeutics has been developed. Recently, cerebrovascular dysfunctions, as a possible cause in the development and progression of sporadic AD, have gained increasing attention. Increasing evidence has indicated the involvement of various alterations in cerebrovascular structure or functions, such as the cerebrovascular microstructure, blood-brain barrier (BBB) integrity, composition of neurovascular unit, cerebrovascular reactivity and cerebral blood flow, in AD pathophysiology and cognitive defects.
Recent findings further highlighted the prevalence of cerebrovascular disorders in Down syndrome patients and added to a growing body of evidence implicating cerebrovascular abnormalities as a core feature of AD rather than a simple comorbidity. Moreover, adrenergic system, including adrenergic receptors and their downstream molecular signaling process, might serve as the key approach to modulate these cerebrovascular abnormalities and progressive neurodegeneration.