B Lymphocytes in Alzheimer’s Disease—A Comprehensive Review

Abstract

Alzheimer’s disease (AD) represents the most common type of neurodegenerative dementia and is characterized by extracellular amyloid-β (Aβ) deposition, pathologic intracellular tau protein tangles, and neuronal loss. Increasing evidence has been accumulating over the past years, supporting a pivotal role of inflammation in the pathogenesis of AD. Microglia, monocytes, astrocytes, and neurons have been shown to play a major role in AD-associated inflammation. However recent studies showed that the role of both T and B lymphocytes may be important. In particular, B lymphocytes are the cornerstone of humoral immunity, they constitute a heterogenous population of immune cells, being their mature subsets significantly impacted by the inflammatory milieu. The role of B lymphocytes on AD pathogenesis is gaining interest for several reasons. Indeed, the majority of elderly people develop the process of “inflammaging”, which is characterized by increased blood levels of proinflammatory molecules associated with an elevated susceptibility to chronic diseases. Epitope-specific alteration pattern of naturally occurring antibodies targeting the amino-terminus and the mid-domain of Aβ in both plasma and cerebrospinal fluid has been described in AD patients. Moreover, a possible therapeutic role of B lymphocytes depletion was recently demonstrated in murine AD models. Interestingly, active immunization against Aβ and tau, one of the main therapeutic strategies under investigation, depend on B lymphocytes. Finally. several molecules being tested in AD clinical trials can modify the homeostasis of B cells. This review summarizes the evidence supporting the role of B lymphocytes in AD from the pathogenesis to the possible therapeutic implications.

B cells and the stressed brain: emerging evidence of neuroimmune interactions in the context of psychosocial stress and major depression

“…Once activated by their cognate pathogenic signal, B cell subset functions within the broader immune response include (1) antigen presentation via major histocompatibility complexes (MHC) to effector immune cells, namely CD4 + or CD8 + T cells, (2) antibody production, and (3) pro- or anti-inflammatory cytokine secretion. These functions coordinate and potentially amplify, restrain, or resolve the broader immune response ( Engler-Chiurazzi et al, 2020 ), and also serve as the foundation for immune memory to a given immunogen ( Plantone et al, 2022 ). IL, Interleukin; TCR, T Cell Receptor; TGF, Transforming Growth Factor; TNF, Tumor Necrosis Factor.…”

“…The next question to be answered is what might B cells be doing in the stressed CNS? The answer may be condition specific as B cells appear to be pathogenic drivers in autoimmunity and Alzheimer’s-like dementia whereas they may be neurorestorative in acute brain or spinal cord injury ( Engler-Chiurazzi et al, 2020 ; Plantone et al, 2022 ; Maheshwari et al, 2023 ; Malone et al, 2023 ).…”

“…As appreciation for the complexity of neuroimmune interactions continues to grow, there is increasing evidence that B lymphocytes may play important roles in central nervous system (CNS) structure and function across the lifespan ( Dwyer et al, 2022 ). Indeed, pathogenic as well as protective effects of B cells have been reported in the context of neurological and spinal cord injuries ( Engler-Chiurazzi et al, 2020 ; Plantone et al, 2022 ; Maheshwari et al, 2023 ; Malone et al, 2023 ), autoimmune diseases ( Jain and Yong, 2022 ), and brain aging, neurodegeneration, and dementia ( Plantone et al, 2022 ), to name just a few examples. Neuroinflammation is a shared feature of many of the neurological diseases in which B cells are implicated ( Bersano et al, 2023 ).…”

Recent Development in the Understanding of Molecular and Cellular Mechanisms Underlying the Etiopathogenesis of Alzheimer’s Disease

“…While the role of B cells is typically thought to be advantageous, recent research on AD animal models has shown that a genetic loss of B cells alone or their depletion at the onset of AD may be beneficial. This highlights that B cells may have a notable detrimental impact on AD progression [ 353 ].…”

Neuroinflammation and Neurodegenerative Diseases: How Much Do We Still Not Know?

“…There is inadequate evidence and inconsistent data in the literature on the function of B lymphocytes, plasma cells, and antibodies in neuroinflammation and ND [54,55], and their contribution in AD pathogenesis needs further investigation. The diverse and obscure points of neuroinflammation and ND [56] could also be clarified.…”