The effects of microglia-associated neuroinflammation on Alzheimer's disease

Abstract

Alzheimer's disease (AD) is defined as a severe chronic degenerative neurological disease in human. The pathogenic mechanism of AD has been convincingly elucidated by the "amyloid cascade hypothesis" with the main focus of the pathological accretion of β-amyloid (Aβ) peptides outside the cell. However, increasing evidence suggests that this hypothesis is weak in explaining the pathogenesis of AD. Neuroinflammation is crucial in the development of AD, which is proven by the elevated levels of inflammatory markers and the identification of AD risk genes relevant to the innate immune function. Here, we summarize the effects of microglia-mediated neuroinflammation on AD, focusing on the temporal and spatial changes in microglial phenotype, the interactions among microglia, Aβ, tau, and neurons, and the prospects and recent advances in neuroinflammation as a diagnostic and therapeutic target of AD.

Keywords: Alzheimer’s disease; microglia activation; neuroinflammation; therapy; β-amyloid.

Figure 1

Different functions of microglia showing the “two-sided” characteristics of microglia and the balance between pro- and anti-inflammation in the progression of CNS neuroinflammation. These microglial phenotypes display different cell surface receptors and secreted factors, among which, by secreting anti-inflammatory cytokines and trophic factors to promote phagocytosis, maintain homeostasis, and nourish nerves. In addition, the surface tightening was activated to cause both synaptic dysfunction and neuronal damage.

Figure 2

Interconnections among microglia, Aβ, tau, and neurons. In their early developmental stages, microglia enhance the phagocytic capacity and generate phagocytoma abnormal material, such as cell debris and misfolded proteins. Subsequently, M2 microglial cells are promoted to release proinflammatory mediators, leading to an inflammatory storm. In this process, the amyloid monomers gradually accumulated to form amyloid plaques. Meanwhile, free tau proteins are phosphorylated and aggregated in neurons to form neurofibrillary tangles. The accumulation of Aβ plaques and the formation of neurofibrillary tangles could positively feedback to microglia to promote the activation of microglia, leading to impaired ability to phagosome foreign objects. AS, abnormal substances (i.e., cell debris and misfolded protein); NFs, neurotrophic factors.