Alzheimer disease (AD) is the most common form of neurodegenerative disease, estimated to contribute 60–70% of all cases of dementia worldwide. According to the prevailing amyloid cascade hypothesis, amyloid-β (Aβ) deposition in the brain is the initiating event in AD, although evidence is accumulating that this hypothesis is insufficient to explain many aspects of AD pathogenesis. The discovery of increased levels of inflammatory markers in patients with AD and the identification of AD risk genes associated with innate immune functions suggest that neuroinflammation has a prominent role in the pathogenesis of AD. In this Review, we discuss the interrelationships between neuroinflammation and amyloid and tau pathologies as well as the effect of neuroinflammation on the disease trajectory in AD. We specifically focus on microglia as major players in neuroinflammation and discuss the spatial and temporal variations in microglial phenotypes that are observed under different conditions. We also consider how these cells could be modulated as a therapeutic strategy for AD. Accumulating evidence indicates important roles for microglial activation and neuroinflammation in Alzheimer disease (AD). Here, Leng and Edison describe the interplay between microglial activation and AD-related pathologies and discuss how microglial priming and activation might influence the trajectory of AD.

Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?

The mammalian CNS is an intricate and fragile structure, which on one hand is open to change in order to store information, but on the other hand is vulnerable to damage from injury, pathogen invasion or neurodegeneration. During senescence and neurodegeneration, activation of the innate immune system can occur. Inflammasomes are signalling complexes that regulate cells of the immune system, which in the brain mainly includes microglial cells. In microglia, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome becomes activated when these cells sense proteins such as misfolded or aggregated amyloid-β, α-synuclein and prion protein or superoxide dismutase, ATP and members of the complement pathway. Several other inflammasomes have been described in microglia and the other cells of the brain, including astrocytes and neurons, where their activation and subsequent caspase 1 cleavage contribute to disease development and progression.

Inflammasome signalling in brain function and neurodegenerative disease

Although the development of mitochondrial therapies has largely focused on diseases caused by mutations in mitochondrial DNA or in nuclear genes encoding mitochondrial proteins, it has been found that mitochondrial dysfunction also contributes to the pathology of many common disorders, including neurodegeneration, metabolic disease, heart failure, ischaemia-reperfusion injury and protozoal infections. Mitochondria therefore represent an important drug target for these highly prevalent diseases. Several strategies aimed at therapeutically restoring mitochondrial function are emerging, and a small number of agents have entered clinical trials. This Review discusses the opportunities and challenges faced for the further development of mitochondrial pharmacology for common pathologies.

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Mitochondria as a therapeutic target for common pathologies.

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by impaired cognitive function due to progressive loss of neurons in the brain. Under the microscope, neuronal accumulation of abnormal tau proteins and amyloid plaques are two pathological hallmarks in affected brain regions. Although the detailed mechanism of the pathogenesis of AD is still elusive, a large body of evidence suggests that damaged mitochondria likely play fundamental roles in the pathogenesis of AD. It is believed that a healthy pool of mitochondria not only supports neuronal activity by providing enough energy supply and other related mitochondrial functions to neurons, but also guards neurons by minimizing mitochondrial related oxidative damage. In this regard, exploration of the multitude of mitochondrial mechanisms altered in the pathogenesis of AD constitutes novel promising therapeutic targets for the disease. In this review, we will summarize recent progress that underscores the essential role of mitochondria dysfunction in the pathogenesis of AD and discuss mechanisms underlying mitochondrial dysfunction with a focus on the loss of mitochondrial structural and functional integrity in AD including mitochondrial biogenesis and dynamics, axonal transport, ER-mitochondria interaction, mitophagy and mitochondrial proteostasis.

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Mitochondria dysfunction in the pathogenesis of Alzheimer's disease: recent advances.

Inflammasomes play a crucial role in innate immunity by serving as signaling platforms which deal with a plethora of pathogenic products and cellular products associated with stress and damage. By far, the best studied and most characterized inflammasome is NLRP3 inflammasome, which consists of NLRP3 (nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3), ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and procaspase-1. Activation of NLRP3 inflammasome is mediated by highly diverse stimuli. Upon activation, NLRP3 protein recruits the adapter ASC protein, which recruits the procaspase-1 resulting in its cleavage and activation, inducing the maturation, and secretion of inflammatory cytokines and pyroptosis. However, aberrant activation of the NLRP3 inflammasome is implicated in various diseases including diabetes, atherosclerosis, metabolic syndrome, cardiovascular, and neurodegenerative diseases; raising a tremendous clinical interest in exploring the potential inhibitors of NLRP3 inflammasome. Recent investigations have disclosed various inhibitors of the NLRP3 inflammasome pathway which were validated through in vitro studies and in vivo experiments in animal models of NLRP3-associated disorders. Some of these inhibitors directly target the NLRP3 protein whereas some are aimed at other components and products of the inflammasome. Direct targeting of NLRP3 protein can be a better choice because it can prevent off target immunosuppressive effects, thus restrain tissue destruction. This paper will review the various pharmacological inhibitors of the NLRP3 inflammasome and will also discuss their mechanism of action.

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Pharmacological Inhibitors of the NLRP3 Inflammasome.

The activation of the NLRP3 inflammasome signaling pathway plays an important role in the neuroinflammation in Alzheimer's disease (AD). In this study, we investigated the effects of JC-124, a rationally designed NLRP3 inflammasome inhibitor, on AD-related deficits in CRND8 APP transgenic mice (TgCRND8). We first demonstrated increased formation and activation of NLRP3 inflammasome in TgCRND8 mice compared to non-transgenic littermate controls, which was inhibited by the treatment with JC-124. Importantly, JC-124 treatment led to decreased levels of Aβ deposition and decreased levels of soluble and insoluble Aβ1-42 in the brain of CRND8 mice which was accompanied by reduced β-cleavage of APP, reduced activation of microglia but enhanced astrocytosis. Oxidative stress was decreased and synaptophysin was increased in the CRND8 mice after JC-124 treatment, demonstrating a neuroprotective effect. Overall, these data demonstrated beneficial effects of JC-124 as a specific NLRP3 inflammasome inhibitor in AD mouse model and supported the further development of NLRP3 inflammasome inhibitors as a viable option for AD therapeutics.

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NLRP3 Inflammasome Inhibitor Ameliorates Amyloid Pathology in a Mouse Model of Alzheimer's Disease.

Mitochondrial dysfunction is an early prominent feature in susceptible neurons in the brain of patients with Alzheimer's disease, which likely plays a critical role in the pathogenesis of disease. Increasing evidence suggests abnormal mitochondrial dynamics as important underlying mechanisms. In this study, we characterized marked mitochondrial fragmentation and abnormal mitochondrial distribution in the pyramidal neurons along with mitochondrial dysfunction in the brain of Alzheimer's disease mouse model CRND8 as early as 3 months of age before the accumulation of amyloid pathology. To establish the pathogenic significance of these abnormalities, we inhibited mitochondrial fragmentation by the treatment of mitochondrial division inhibitor 1 (mdivi-1), a mitochondrial fission inhibitor. Mdivi-1 treatment could rescue both mitochondrial fragmentation and distribution deficits and improve mitochondrial function in the CRND8 neurons both in vitro and in vivo. More importantly, the amelioration of mitochondrial dynamic deficits by mdivi-1 treatment markedly decreased extracellular amyloid deposition and Aβ1-42/Aβ1-40 ratio, prevented the development of cognitive deficits in Y-maze test and improved synaptic parameters. Our findings support the notion that abnormal mitochondrial dynamics plays an early and causal role in mitochondrial dysfunction and Alzheimer's disease-related pathological and cognitive impairments in vivo and indicate the potential value of restoration of mitochondrial dynamics as an innovative therapeutic strategy for Alzheimer's disease.

Jun Yin

Papers

NLRP3 Inflammasome Inhibitor Ameliorates Amyloid Pathology in a Mouse Model of Alzheimer's Disease.

Inhibition of mitochondrial fragmentation protects against Alzheimer's disease in rodent model.