TL;DR
This network is interconnected, and understanding it is crucial in the creation of therapies that attempt to restore proteostasis, inhibit inflammation, and increase neurotrophic signalling to delay or prevent PD progression.
It is proposed that the α-synuclein pathology starts in the gut with the non-motor symptoms, and then it propagates to the brain via the vagus nerve causing motor symptoms, which has emerged as an attractive target for immunotherapies.
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the pathological accumulation of Lewy bodies composed predominantly of aggregated α-synuclein (αSyn). Despite decades of progress in genetics and neuropathology, the mechanisms driving disease initiation and progression remain incompletely understood, and no disease-modifying therapy has yet demonstrated conclusive efficacy. Neuroinflammation and metabolic dysfunction have emerged as two central and mechanistically intertwined pillars of PD pathogenesis. We propose an integrative model in which these processes function not merely in parallel, but as mutually reinforcing components of a self-amplifying pathological circuit, while acknowledging that this model remains to be fully validated and that alternative causal architectures are possible. This review systematically addresses the mechanistic coupling between neuroinflammation and metabolic dysregulation in PD, covering: (1) the molecular basis of innate immune activation via DAMPs, pattern recognition receptors, and inflammasome signaling; (2) microglial metabolic reprogramming and the NLRP3/NF-κB inflammatory axis; (3) αSyn-driven innate and adaptive immune responses; (4) mitochondrial dysfunction and oxidative stress as bidirectional amplifiers; (5) the gut-brain axis as a conduit for peripheral immunometabolic disruption; (6) the AMPK/mTOR/HIF-1α molecular network integrating metabolism and inflammation; (7) sphingolipid metabolism and the GBA-lysosomal axis; and (8) translational evidence from animal models and randomized controlled trials. A concise section integrates key fluid biomarkers as clinical surrogates of the underlying mechanisms.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the intracellular accumulation of alpha-synuclein (α-syn) aggregates. Historically, research has focused on neuronal mechanisms; however, growing evidence indicates that the progression of neurodegeneration is influenced by changes in the brain microenvironment, particularly through the dynamic interplay between microglia and the extracellular matrix (ECM). ECM in the central nervous system is an organized network of structural proteins, glycoproteins, and proteoglycans that encases neurons and glial cells, regulating processes such as synaptic stability, neural plasticity, and intercellular signaling. In PD, the aggregation of α-syn and neuronal damage induce sustained microglial activation, which can alter ECM structure. Activated microglia release proteases, including matrix metalloproteinases and cathepsins, which can degrade critical ECM components such as collagens, laminins, and proteoglycans. This remodeling can modify synaptic architecture, regulate cellular signaling, and disrupt neuron-glia interactions, fostering an environment conducive to dopaminergic degeneration. Furthermore, ECM remodeling and microglial activation exhibit regional variability within the brain. Regions notably prone to degeneration, such as the SNpc and striatum, display significant alterations in matrix organization and inflammatory activity, while other dopaminergic regions, including the ventral tegmental area, show increased resilience. We suggest that microglia-mediated ECM remodeling serves as a mechanistic link between neuroinflammation and neuronal susceptibility in PD. This review consolidates the existing knowledge on microglial modulation of ECM dynamics during neurodegeneration, explores regional differences in these processes, and evaluates their significance as possible treatment targets.
Alzheimer's disease (AD) is a progressively debilitating neurodegenerative condition characterized by the accumulation of amyloid-β (Aβ), tau pathology, synaptopathy, and neuron loss. Recent studies suggest that Neuroinflammation is a critical part of the disease process rather than an accompanying feature of the mentioned pathological changes. Microglia, the immune cells of the central nervous system, respond to amyloid-beta and pathological tau and exhibit functional alterations leading to the transition from their initial anti-inflammatory and neuroprotective function to chronic inflammation. Persistent activation of microglia is linked with the inability to clear abnormal proteins, excessive complement-dependent synaptic loss, secretion of cytokines, activation of astrocytes, and neuronal damage. Various inflammatory pathways play their roles, and one of the most prominent is the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome. The activation of the NLRP3 inflammasome leads to the recruitment of apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1 activation, followed by interleukin-1β (IL-1β) and IL-18 maturation and gasdermin D (GSDMD) cleavage, contributing to pyroptosis and inflammatory processes. The current review will cover changing role of microglia in AD progression, interactions between Aβ, tau, and inflammatory signaling pathways as well as molecular mechanisms of NLRP3 Inflammasome activation. Furthermore, it will discuss new approaches that could be used for modulations of NLRP3 inflammasome signaling, including selective small molecule inhibition, caspase-1 targeting, natural compound use, repurposed drugs, and new drug delivery systems. Specifically, the ability to cross blood-brain barrier (BBB), safety, translational challenges, and dissimilarity between animal models and humans' AD will be discussed in this context. Overall, targeting dysregulated Neuroinflammation, including NLRP3 inflammasome activation, could serve as an alternative approach to existing protein-directed treatment methods.
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