The neuroimmune axis of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder with multifaceted neuropathological features, including β-amyloid plaques, neurofibrillary tangles, and neuroinflammation. Over the past decade, emerging evidence has implicated both beneficial and pathological roles for innate immune genes and immune cells, including peripheral immune cells such as T cells, which can infiltrate the brain and either ameliorate or exacerbate AD neuropathogenesis. These findings support a neuroimmune axis of AD, in which the interplay of adaptive and innate immune systems inside and outside the brain critically impacts the etiology and pathogenesis of AD. In this review, we discuss the complexities of AD neuropathology at the levels of genetics and cellular physiology, highlighting immune signaling pathways and genes associated with AD risk and interactions among both innate and adaptive immune cells in the AD brain. We emphasize the role of peripheral immune cells in AD and the mechanisms by which immune cells, such as T cells and monocytes, influence AD neuropathology, including microglial clearance of amyloid-β peptide, the key component of β-amyloid plaque cores, pro-inflammatory and cytotoxic activity of microglia, astrogliosis, and their interactions with the brain vasculature. Finally, we review the challenges and outlook for establishing immune-based therapies for treating and preventing AD.

Keywords: Alzheimer’s disease; Heterogeneity; Immune system; Neuroimmune; β-amyloid.

Fig. 1

Neuroimmune interactions in AD neuropathology. AD is a heterogeneous and multifactorial complex neurodegenerative disease that is characterized by the abnormal aggregation of extracellular β-amyloid plaques and intracellular neurofibrillary tangles. This leads to neuronal cell death, synaptic degradation, and gliosis (microglia and astrocytes), further exacerbating neurodegeneration and ultimately leading to dementia. Under homeostatic conditions, microglia have a predominantly protective role, including phagocytosis and degradation of Aβ, secretion of anti-inflammatory cytokines, and neural network remodeling. However, excessive β-amyloid deposition and neuronal cell death can trigger robust pro-neuroinflammatory activation of microglia, leading to the release of pro-inflammatory cytokines and complement. A vicious cycle of neuropathology, pro-inflammatory glial activation, and excessive neurodegeneration ensues. This pathological cycle affects the BBB integrity and lymphatic drainage, which leads to immune cell infiltration (e.g., T cells) in the brain parenchyma and border zone, immune cell activation, antigen accumulation, and TCR clonal expansion. In this neuroimmune axis model, immunopathogenesis changes can therefore serve as a foundation for designing and developing of disease-modifying therapies for AD. APC, antigen-presenting cells; TCR, T cell receptor

Fig. 2

Investigational drugs and proposed targets for the treatment of Alzheimer’s disease and related dementia (ADRD), focusing on those that have been approved or progressed to Phase 2/3 or beyond in U.S. clinical trials. This up-to-date dataset was obtained from alzforum.org, a resource provided by FBRI LLC