As is the case for other neurodegenerative conditions, Alzheimer’s disease has a strong inflammatory component. Even if other mechanisms are important, and there is very strong evidence for this to be the case, dysregulation of immune cells in the brain contributes notably to the progression of the condition. As recent work demonstrates, this dysregulation may arise in large degree because of the inflammatory signaling generated by senescent cells, but these errant cells are are not the only way in which the aged, damaged immune system can become more inflamed and thus more hostile towards the tissues it is supposed to help maintain.
Inflammation for short periods of time is a necessary part of the immune response, and assists in the removal of pathogens and regeneration of structural damage. That same inflammation extended over the long-term, as occurs in aging, disrupts many vital processes in a wide range of cell populations and tissues. This is harmful in any tissue, but the resident immune cells of the central nervous system play important roles in all sorts of processes vital to the normal operation of the brain, such as the creation and maintenance of synaptic connections between neurons.
Pathologically, Alzheimer’s disease (AD) brains harbor amyloid plaques that contain extracellularly deposited amyloid β (Aβ) from cleaved amyloid precursor protein, and neurofibrillary tangles formed by intracellular accumulation of hyperphosphorylated and misfolded tau protein. These characteristic entities inspired a leading theory that centers on the loss of proteostasis within the brain, which instigates the pathogenic course of AD. The Amyloid Cascade Hypothesis has guided numerous studies in the past two decades, which helped reveal insights of the neuronal properties and pathological events initiated by Aβ and subsequently by tau aggregation.
However, it is clear that late-onset Alzheimer’s disease (LOAD) is collectively modified by numerous genetic factors that govern diverse cellular and molecular pathways, including many genes involved in the immune responses. Consequently, the Neuroinflammation Hypothesis emphasizes the dysregulation of central nervous system (CNS) immune response as a key factor in the etiology of neurodegenerative diseases. In recent years, neuroinflammation is increasingly recognized as an integral and critical contributor in AD pathogenesis.
The role played by the immune system in AD pathogenesis is prominent but is by no means limited to the brain. Copious evidence from clinical and experimental research suggests an influential, yet largely underappreciated, force in AD pathogenesis: systemic immune signals originating outside the brain. Despite genetic evidence implicating adaptive immunity in AD, it remains ill-defined how adaptive immune cells with limited presence inside the parenchyma exert their effects on AD pathologies and cognitive functions. Nevertheless, T cells have been shown to participate in other neurodegenerative diseases, such as Parkinson’s disease and amyotrophic lateral sclerosis.
Many inconsistent results have been reported on the impacts of T cell subsets on CNS pathogenesis in Aβ-based experimental models. Noticeably missing at this time is the examination of tau-specific T cells and the possible involvement of Treg cells in tau pathology, a major gap in understanding the participation of the adaptive immune arm in AD pathogenesis. Despite the technical challenge to study rare cells, new technologies such as high-dimensional single-cell analysis should significantly improve the quantification and classification of diverse immune cell populations in the AD brain. Whether T cells and B cells, self-reactive or bystanders, afford protective immune surveillance or pathogenic immune attack requires thorough delineation.