Neuroinflammation as a mechanism linking hypertension with the increased risk of Alzheimer's disease

Alzheimer's disease,the most common type of dementia among older adults,currently cannot be prevented or effectively treated.Only a very small percentage of Alzheimer's disease cases have an established genetic cause.The majority of Alzheimer's disease cases lack a clear causative event,but several modifiable factors have been associated with an increased risk of this disease.Persistent midlife hypertension is one such risk factor,which can be effectively controlled through changes in diet,lifestyle,and antihypertensive drugs.Identifying molecular mechanisms linking modifia ble risk factors with the increased risk of Alzheimer's disease could enhance our understanding of this disease and lead to identification of novel targets and thera peutic approaches for effective treatments.Glial cell-driven neuroinflammation is one of the key pathological features of Alzheimer's disease.In this review,we illustrate that neuroinflammation could also be one of the possible mechanisms linking hypertension and Alzheimer's disease.Animal studies have demonstrated that chronically elevated blood pressure leads to adverse glial activation and increased brain inflammatory mediators.We highlight damage to cerebral microvasculature and locally activated renin-angiotensin system as the key pathogenetic mechanisms linking hypertension to neuroinflammation and the accompanying neurodegenera tion.The role of tumor necrosis factor-αand interleukin-1βas pro-inflammatory signaling molecules providing this link is discussed.We also summa rize the available experimental data indicating that neuroinflammatory changes and glial activation can be reversed by several diffe rent classes of antihypertensive medicines.These studies suggest antihypertensives could be beneficial in Alzheimer's disease not only due to their a bility to control the blood pressure,but also due to their antineuroinflammatory effects.Confirmation of these observations in human subjects is required and recent advances in the brain imaging techniques allowing visualization of both microglia and astrocyte activation will be essential for this research.

Possible role of microparticles in neuroimmune signaling of microglial cells

Aim:Submicron fragments termed microparticles(MPs),derived from all major central nervous system cell types including neurons and glia(microglia,astrocytes,oligodendrocytes),have emerged as novel intercellular signaling agents.This study tested the hypothesis that MPs derived from activated microglia,which represent the mononuclear phagocyte system in the brain,could induce pro-inflammatory and cytotoxic responses of microglia in an autocrine or paracrine manner.Methods:Human THP-1 monocytic cells were used to model human microglia.MPs derived from these cells were reapplied to THP-1 cells and their secretion of neurotoxins and cytokines was measured.Results:When exposed to lipopolysaccharide(LPS)or mitochondrial transcription factor A in combination with interferon(IFN)-γ,THP-1 cells released MPs.When reapplied to THP-1 cells,MPs induced the release of secretions that were toxic to human SH-SY5Y neuroblastoma cells,as well as monocyte chemoattractant protein-1.The cytotoxicity of THP-1 cells induced by MPs derived from IFN-γplus LPS-treated THP-1 donor cells was enhanced in the presence of IFN-γ.The MPs released by THP-1 cells were not directly toxic towards SH-SY5Y cells.Conclusion:Our data support the hypothesis that activated microglia-derived MPs could act as signaling agents that are recognized by microglia to cause pro-inflammatory and cytotoxic responses.