Alzheimer's disease progresses from the slow accumulation of amyloid-β plaques, that appear to cause comparatively mild dysfunction, to the accumulation of neurofibrillary tangles composed of altered tau protein, which cause major dysfunction and cell death in the later stages of the condition. Along the way chronic inflammation in brain tissue arises, along with dysfunctional behavior on the part of immune cells in the brain. As is the case in the open access review paper here, one can take these facts and suggest that amyloid-β deposition causes immune cell dysfunction, which in turn causes tau deposition. There is certainly evidence to support this view, such as the recent studies showing that clearance of senescent microglia turns back tau pathology and inflammation in animal models of Alzheimer's disease. This is probably just one of several lines of cause and consequence, however: Alzheimer's is a very complex condition.
Neuroinflammation is considered one of the cardinal features of Alzheimer's disease (AD). Neuritic plaques composed of amyloid β and neurofibrillary tangle-laden neurons are surrounded by reactive astrocytes and microglia. Exposure of microglia, the resident myeloid cell of the central nervous system (CNS), to amyloid β causes these cells to acquire an inflammatory phenotype. While these reactive microglia are important to contain and phagocytose amyloid plaques, their activated phenotype impacts CNS homeostasis.
In rodent models, increased neuroinflammation promoted by overexpression of proinflammatory cytokines can cause an increase in hyperphosphorylated tau and a decrease in hippocampal function. The peripheral immune system can also play a detrimental or beneficial role in CNS inflammation. Systemic inflammation can increase the risk of developing AD dementia, and chemokines released directly by microglia or indirectly by endothelial cells can attract monocytes and T lymphocytes to the CNS. These peripheral immune cells can aid in amyloid β clearance or modulate microglia responses, depending on the cell type.
The contribution of specific pro-inflammatory and anti-inflammatory factors in AD is not straightforward, especially since the evaluation of cognition, amyloid β pathology, and neurofibrillary tangles yields conflicting results in mouse models. Furthermore, translating rodent studies that have modulated expression of specific cytokines in the CNS is challenging. In addition, studies that have shown promise, such as the beneficial effects of pioglitazone in mouse models of AD, do not always prove effective in humans.
Nonetheless, the immune response is deeply tied to the development of pathology, and with advancing technologies, we are able to more fully dissect the complexity of this response and the effector cells that carry it out. Our knowledge of how microglia and peripheral immune cells interact has proved invaluable in understanding how this delicate balance goes awry in disease. Immunomodulation in AD offers multiple, promising pathways of investigation that might lead to therapeutics that can prevent or halt the development of amyloid and tau pathology and cognitive decline.