A recent review published in the Journal of Clinical Investigation highlights the complex and sometimes paradoxical role of the immune system in neurodegenerative diseases, suggesting that immune responses may both initiate disease processes and contribute to their progression.
Neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are increasingly understood as disorders not only of protein aggregation but also of immune dysregulation. Within the central nervous system (CNS), resident immune cells, particularly microglia and astrocytes, play a critical role in maintaining homeostasis, including preserving the integrity of the blood–brain barrier (BBB) and clearing cellular debris. Under physiological conditions, these cells exert neuroprotective functions, but in disease states, their responses can become maladaptive and self-perpetuating.
The review emphasizes that abnormal protein aggregates, including phosphorylated tau, amyloid beta (Aβ), and α-synuclein, act as danger-associated molecular patterns (DAMPs). These molecules activate innate immune receptors such as Toll-like receptors (TLR2 and TLR4), initiating inflammatory signaling cascades. This leads to the release of pro-inflammatory cytokines, including TNF-α and interleukins, which can exacerbate neuronal injury and accelerate disease progression. In addition to TLR signaling, other innate immune pathways such as the NLRP3 inflammasome and the cGAS-STING pathway are implicated in sustaining chronic neuroinflammation.
The review highlights a dual role of immune activation. Experimental evidence shows that complete inhibition of certain immune pathways may worsen outcomes, leading to increased amyloid accumulation and faster cognitive decline. This suggests that early or controlled immune responses may facilitate clearance of toxic proteins and support neuronal survival, whereas prolonged or excessive activation contributes to neurotoxicity.
The Receptor for Advanced Glycation End Products (RAGE) emerges as a common mediator across multiple neurodegenerative diseases. Increased expression of RAGE has been associated with enhanced neuroinflammation and more rapid cognitive decline, while its suppression appears to confer neuroprotective effects in experimental models.
Genetic studies further reinforce the central role of immune mechanisms. Variants in the TREM2 gene, which regulates microglial activation and phagocytosis, significantly increase the risk of Alzheimer’s disease, with an effect size comparable to that of the well-established APOE ε4 allele. These findings underscore the importance of microglial function in modulating disease susceptibility and progression.
Adaptive immunity also plays a nuanced role. CD4+ T cells have demonstrated protective effects in Alzheimer’s disease models by supporting neuroprotective immune responses, yet they can contribute to inflammation and neuronal damage in Parkinson’s disease. Similarly, CD8+ T cells exhibit context-dependent roles, participating in both neurodegenerative and protective processes depending on their activation state and microenvironment.
Aging remains the most significant risk factor, as it is associated with immunosenescence and a chronic low-grade inflammatory state often termed “inflammaging.” This altered immune landscape predisposes the brain to exaggerated and dysregulated responses. Environmental factors such as traumatic brain injury and viral infections may further perturb immune balance, increasing vulnerability to neurodegeneration.
The review underscores that neurodegenerative diseases arise from a dynamic interplay between immune dysregulation, genetic predisposition, and environmental triggers. The timing, intensity, and context of immune activation appear to determine whether these responses are protective or harmful.
These insights have significant therapeutic implications. Rather than broadly suppressing inflammation, future strategies may need to focus on selectively modulating immune pathways enhancing protective responses while limiting chronic neuroinflammation. Such precision immunomodulation could pave the way for disease-modifying therapies capable of slowing or preventing neurodegenerative progression without unintended adverse effects.
References
- Latour YL, McGavern DB. Immune signaling and function in neurodegeneration. Journal of Clinical Investigation. 2026 Apr 15;136(8):e199850. doi:10.1172/JCI199850