A shared hallmark of age-related neurodegenerative diseases is the chronic activation of innate immune cells, which actively contributes to the neurodegenerative process. In Alzheimer’s disease, this inflammatory milieu exacerbates both amyloid and tau pathology. A similar abnormal inflammatory response has been reported in Parkinson’s disease, with elevated levels of cytokines and other inflammatory intermediates derived from activated glial cells, which promote the progressive loss of nigral dopaminergic neurons. Understanding the causes that support this aberrant inflammatory response has become a topic of growing interest and research in neurodegeneration, with high translational potential. It has been postulated that the phenotypic shift of immune cells towards a proinflammatory state combined with the presence of immunogenic cell death fuels a vicious cycle in which mitochondrial dysfunction plays a central role. Mitochondria and mitochondria-generated reactive oxygen species are downstream effectors of different inflammatory signaling pathways, including inflammasomes. Dysfunctional mitochondria are also recognized as important producers of damage-associated molecular patterns, which can amplify the immune response. Here, we review the major findings highlighting the role of mitochondria as a checkpoint of neuroinflammation and immunogenic cell deaths in neurodegenerative diseases. The knowledge of these processes may help to find new druggable targets to modulate the inflammatory response.

Microglia play a significant role in the development and progression of Alzheimer's disease (AD). These brain-resident immune cells efficiently clear neurotoxic amyloid beta (Aβ) peptides; however, chronic activation may overwhelm their protective abilities, resulting in persistent neuroinflammation. The causes of aberrant microglial activation in AD remain elusive. Emerging evidence indicates that copper (Cu) accumulation, which can arise from prolonged exposure to various environmental sources, modifies the innate immune response in AD. Here, we sought to explore the mechanisms by which Cu overload regulates the microglial phenotype when exposed to Aβ. Our findings showed that exposure to sublethal doses of Cu led to the accumulation of this transition metal in the mitochondria. Elevated mitochondrial Cu (mtCu) levels were accompanied by reduced mitochondrial glutathione (mtGSH) and high oxidative stress, leading to Aβ-induced inflammasome activation through the release of oxidized mitochondrial DNA (ox-mtDNA). Moreover, increased intracellular Cu levels enhanced cholesterol biosynthesis and facilitated its transport to mitochondria. The combination of elevated cholesterol and mitochondrial oxidative stress hindered the ability of microglia to phagocytose Aβ effectively. As expected, conditioned medium from Cu-activated microglia reduced neuronal viability. The neurotoxicity caused by Cu-overloaded microglia was prevented by inhibiting inflammasome activation and restoring mtGSH levels. In conclusion, our study outlines a mechanistic pathway by which chronic exposure to environmental Cu may lead to neuroinflammation and Aβ accumulation in AD, underscoring the crucial role of mitochondrial oxidative stress.

Background: Changes in copper (Cu) homeostasis have been consistently linked to Alzheimer’s disease (AD). Cu can bind to amyloid beta (Ab) and enhance neurotoxicity through the generation of reactive oxygen species.Furthermore, Cu possesses both pro‐ and anti‐inflammatory properties mediated by its proximity to amyloid plaques. A key pro‐inflammatory pathway reported induced in AD is the NLRP3 inflammasome that leads to the activation of inflammatory caspases, mainly caspase‐1, and the processing of interleukin‐1b (IL‐1b) into its active form. This work aimed to assess the synergistic interaction between Cu overload and the Aβ‐induced inflammatory response on microglia and evaluate the underlying mechanisms.Method: Using immortalized mouse microglia (SIM‐A9) exposed to 1 uM Ab and subtoxic doses of Cu (50, 100 and 200 uM) for 24 h, we assessed ROS by fluorometry using Dihydroethidium (DHE), expression levels of inflammasome‐related proteins by western blot and RT‐PCR selfie, and phagocytosis of microglia by confocal microscopy using fluorescent microbeads (1µm). To assess inflammasome assembly, cells were transfected with the pLEX‐MSC‐ASC‐GFP vector and ASC speckle formation was analyzed by confocal microscopy.Results: Cu treatment induced IL‐1b and Nlrp3 expression, which was further enhanced when combined with Aβ. While untreated cells showed homogeneously distributed ASCs in the cytosol, we found “speckles” of ASCs in those treated with Cu and Cu plus Aβ, in the vicinity of the nucleus, indicating involvement of the inflammasome. Cu treatment increased total cholesterol (Cho) and mitochondrial Cho levels and was accompanied by a significant decrease in mitochondrial GSH levels. Accordingly, ROS levels increased significantly with the combination of Cu and Aβ. Oxidative stress was prevented by glutathione ester (GSHee) treatment and the use of mitochondrial antioxidant agents (MitoTEMPO and MitoQ). In parallel, we analyzed microglia phagocytosis by confocal microscopy. Microbead uptake was significantly impaired after Cu overload but was partially restored by pretreatment with GSHee, which recovered mitochondrial GSH and reduced oxidative stressConclusion: High Cu levels regulate the microglial response to Aβ by boosting mitochondrial oxidative stress, resulting in inflammasome activation with the release of pro‐inflammatory cytokines such as IL‐1b) and decreased phagocytic capacity, which may contribute to the accumulation and formation of Aβ deposits.