MOLECULAR MECHANISMS OF NEUROINFLAMMATION IN ALZHEIMER'S DISEASE: UNDERSTANDING THE INTERPLAY BETWEEN MICROGLIA, CYTOKINES, AND SYNAPTIC DYSFUNCTION

Abstract

Neuroinflammation is one of the major pathological hallmarks in AD, and it is primarily the result of microglial activation, dysregulated cytokines, and synaptic dysfunction. This review discusses the molecular mechanisms of neuroinflammatory response at AD while focusing on microglia, astrocytes, and the complement system in synapse elimination and cognitive deficit as they relate to synaptic loss and cognitive impairment. It offers an insight into microglia-mediated complement activation C1q and C3 and their contribution to excessive pruning of synapses, resulting in neuronal loss. Similarly, neurodegeneration is exacerbated through impairment of synaptic plasticity and neurotransmitter disbalance by cytokines like IL-1β, TNF-α, and IL-6. TREM2 is one of the prime microglial receptors involved in modifying immune responses and clearing amyloid-beta (Aβ); however, TREM2 mutations impair its function and put neurons at risk of inflammation and damage. Astrocytes further add to neuroinflammation through the release of proinflammatory mediators and the disruption of glutamate homeostasis. Although imaging and modern artificial intelligence tools have conveyed some understanding of microglial dynamics, considerable gaps remain regarding microglial subtype heterogeneity and long-term results of neuroinflammatory pathway targeting in this aspect. Thus, attention should be focused on the modulation of TREM2 activation, complement inhibition, and cytokine modulation in upcoming therapeutic strategies to achieve neuroinflammation-based action without compromising critical immune functions. Such knowledge on the part of neuroinflammation and its role in synaptic dysfunction in AD will enlighten the basis for intervention in slowing down disease progression while preserving cognitive function.