Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression

Abstract

Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in discrete areas of the central nervous system (CNS). The mechanism(s) underlying their progressive nature remains unknown but a timely and well-controlled inflammatory reaction is essential for the integrity and proper function of the CNS. Substantial evidence has documented a common inflammatory mechanism in various neurodegenerative diseases. We hypothesize that in the diseased CNS, interactions between damaged neurons and dysregulated, overactivated microglia create a vicious self-propagating cycle causing uncontrolled, prolonged inflammation that drives the chronic progression of neurodegenerative diseases. We further propose that dynamic modulation of this inflammatory reaction by interrupting the vicious cycle might become a disease-modifying therapeutic strategy for neurodegenerative diseases.

Figure 1

Inflammation determines the progression and outcome of neurodegenerative diseases. Insults to the central nervous system (CNS; e.g. trauma or environmental toxins) or genetic predisposition can directly trigger neuronal lesions. Injured neurons activate the surrounding microglia through noxious self-compounds in the extracellular milieu, such as membrane breakdown products, abnormally processed or aggregated proteins (e.g. α-synuclein and β-amyloid), imbalanced neurotransmitters (e.g. elevated glutamate) and released or leaked cytosolic compounds (e.g. α-synuclein and neuromelanin; highlighted in light orange). Activated microglia produce and secrete a spectrum of inflammatory mediators, such as cytokines, eicosanoids, chemokines, reactive free radicals and proteases. Some environmental risk factors can directly activate microglia or cause systemic inflammation, which might in turn impact on local CNS inflammation, including microglial activation (highlighted in red and light orange). The inflammatory mediators not only can further modulate microglial activity but also can influence the fate of surrounding neurons. Normally, in addition to self-controlling innate immune mechanisms, there is a constant, complex interaction between the immune, endocrine, and nervous systems to maintain proper immune homeostasis. Under strict regulation, inflammation is normally self-limiting and is essential for CNS integrity. Some aspects of the inflammatory process are actually beneficial, such as the removal of cellular debris, the elimination of toxic substances and the release of neurotrophic factors by activated microglia (highlighted in green and blue colors). Escaping from its tight control, the immune response can become exaggerated and destructive, and turns into chronic persistent inflammation that drives progressive neurodegeneration. Thus, regardless of the type of the initial lesion, neuronal damage and uncontrolled inflammation amplify each other, inducing a vicious self-propagating cycle that causes the chronic progression of neurodegenerative diseases. α-syn, α-synuclein; CNS, central nervous system; IL-1, interleukin 1; IL-10, interleukin 10; TNF-α, tumour necrosis factor α.