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Novel targets in Alzheimer's disease: A special focus on microglia
Claudia Balducci1, Gianluigi Forloni1
1Biology of Neurodegenerative Disorders Lab, Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Abstract:
Several years after the intriguing novelty in the β-amyloid (Aβ) cascade hypothesis, where the Aβ oligomers emerged as the most detrimental species in the neuropathogenic process of Alzheimer's disease (AD) in place of fibrillar plaques, more recently innate immune system have come on stage as the other prominent factor. Neuroinflammation apparently contributes to AD eziopathogenesis, in large part through overactivation of microglia cells. Genetic and experimental studies strongly support the contribution of the immune system to increasing the risk of AD and participating in its progression. Besides the central immune response mediated by resident microglial cells, peripheral immune challenges may have profound negative effects on brain physiology as well, such as those originating from the gut microbiota. Despite the initial immune response to defend the organism, perpetuation seemingly turns into a chronic detrimental phenomenon that contributes to neuronal dysfunction and exacerbation of the disease. Several new immune-druggable targets are now under investigation, but much still remains to be defined about their precise role and whether and how their physiological activity changes in the injurious context of AD. From a therapeutic perspective, we can undoubtedly consider that AD is no longer solely an Aβ pathology, but rather a multifaceted disorder calling for multi-target therapies. New therapies fighting AD must still counteract Aβ but must also restore appropriate immune defences by tempering maladaptive factors and enabling beneficial responses.
Insights
Alzheimer's disease involves more than just amyloid-beta. Neuroinflammation, driven by the immune system, significantly contributes to disease progression and neuronal damage, necessitating multi-target therapies.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- The amyloid-beta (Aβ) cascade hypothesis initially focused on Aβ oligomers as key drivers of Alzheimer's disease (AD) neuropathogenesis.
- Emerging evidence highlights the critical role of the innate immune system and neuroinflammation, particularly microglial cell overactivation, in AD pathogenesis.
- Both central and peripheral immune system dysfunctions, including those influenced by gut microbiota, are implicated in increasing AD risk and disease progression.
Purpose of the Study:
- To explore the multifaceted role of neuroinflammation and the immune system in Alzheimer's disease (AD) pathogenesis.
- To discuss the implications of immune system involvement for AD diagnosis and therapeutic strategies.
- To emphasize the need for multi-target therapies that address both Aβ pathology and immune dysregulation.
Main Methods:
- Review of genetic and experimental studies investigating the immune system's contribution to AD.
- Analysis of the role of microglia and peripheral immune challenges in brain physiology.
- Examination of current and potential immune-druggable targets in AD.
Main Results:
- Neuroinflammation, driven by overactivated microglia, is a significant factor in AD pathogenesis.
- Immune system activation, while initially protective, can become a chronic detrimental process exacerbating neuronal dysfunction.
- Peripheral immune challenges, such as those from gut microbiota, negatively impact brain health in AD.
Conclusions:
- Alzheimer's disease is a complex, multifaceted disorder involving both Aβ pathology and immune system dysregulation.
- Therapeutic strategies must evolve beyond solely targeting Aβ to include modulation of the immune response.
- Future AD therapies should aim to counteract Aβ while restoring appropriate immune defenses and mitigating maladaptive immune factors.