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.

Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

“…The potential for T-cell infiltration into the brain with aging and AD has been a question in the field for at least a decade 83,84 . Aging causes an increase in CD8+ T-cells in mice 85 which has subsequently been characterized as tissue resident Tcells (Trm) but the characterization of infiltrating T-cells with aging and AD is an ongoing and controversial topic (for review see 84,[86][87][88] ). The data on T-cell infiltration into the parenchyma with non-pathological aging is varied with reports ranging from no or limited infiltration to significant numbers [89][90][91] .…”

Comparative gene regulatory network analysis in Alzheimer’s disease and major depressive disorder identifies shared core regulatory circuits

“…This has been seen for the ABCA7 and INPP5D genes, of which the latter is also a part of this module. INPP5D encodes for the SHIP1 protein, which has been implicated in AD 62,67 . It acts as a negative regulator of myeloid cell proliferation/survival and chemotaxis, immune cells homeostasis, it regulates macrophage programming, phagocytosis and activation, and neutrophil migration 68 .…”

“…Phagocytosis is decreased in this subtype 61 . Higher levels of T-cell infiltration are seen in AD patients, however, their exact role remains unclear 62 . The TFs of this module were IKZF1, NFATC2 and RUNX1.…”

Basic Mechanisms of Brain Injury and Cognitive Decline in Hypertension

“…While microglia are commonly known in neurodegeneration for their role in neuroinflammatory processes, and particularly contributing to Alzheimer’s disease pathology, 77 they have recently been implicated in cerebrovascular function. 78 A subpopulation of microglia, known as juxtavascular or capillary-associated microglia, 78 are located in close proximity of brain microvessels, specifically in direct contact with the capillary basement membrane without disrupting astrocytic endfeet or pericyte coverage of microvessels.…”