Does Peripheral Blood Amyloid-β Contribute to Alzheimer's Disease via Inflammatory Mechanisms?
Amyloid-β is found in the bloodstream and blood vessels as well as in the brain, and an increase in this peripheral amyloid-β is noted in Alzheimer's disease patients who exhibit the characteristic amyloid-β aggregates in their brains. Current thinking is that there is a dynamic equilibrium between amyloid-β in the brain and body, and based on this view some success has been achieved in reducing amyloid-β in the brain by clearing amyloid-β in the rest of the body. Does this peripheral amyloid-β contribute to the onset of Alzheimer's disease in other ways, however? Researchers here suggest that it may increase the burden of systemic chronic inflammation, known to be involved in Alzheimer's disease pathology.
A key pathological factor of Alzheimer's disease (AD), the most prevalent form of age-related dementia in the world, is excessive β-amyloid protein (Aβ) in extracellular aggregation in the brain. And in the peripheral blood, a large amount of Aβ is derived from platelets. So far, the causality between the levels of peripheral blood Aβ and its aggregation in the brain, particularly the role of the peripheral blood Aβ in the pathology of AD, is still unclear. And the relation between the peripheral blood Aβ and tau tangles of brain, another crucial pathologic factor contributing to the pathogenesis of AD, is also ambiguous.
More recently, the anti-Aβ monoclonal antibodies are approved for treatment of AD patients through declining the peripheral blood Aβ mechanism of action to enhance plasma and central nervous system (CNS) Aβ clearance, leading to a decreased Aβ burden in brain and improving cognitive function, which clearly indicates that the levels of the peripheral blood Aβ impacted on the Aβ burden in brain and involved in the pathogenesis of AD. In addition, the role of peripheral innate immune cells in AD remains mostly unknown and controversial.
In the present review, we summarize recent studies on the roles of peripheral blood Aβ and the peripheral innate immune cells in the pathogenesis of AD. In the early stage of disease, the peripheral Aβ is involved in the pathogenesis of AD through activating innate immune cells and promoting them to secretion of inflammatory cytokines and molecules leading to enhancing the blood-brain barrier (BBB) permeability or damage the BBB. In the late stage, the peripheral Aβ may activate the peripheral and central inflammatory processes by affecting the proliferation and differentiation of innate immune cells. The recruitment of the peripheral innate immune cells may lead to increased production of proinflammatory cytokines by microglia, promoting the recruitment of more peripheral innate immune cells to move to the Aβ plaques of brain.