The emerging role of astrocytes in spatial cognition, action and Alzheimer’s disease

Biochemical modulators of synaptic plasticity: New horizons in Alzheimer's disease treatment

Graphical Abstract This is a visual representation of the abstract. Synaptic dysfunction is the earliest and most critical pathological feature of Alzheimer's disease (AD), directly contributing to cognitive decline. This review provides an integrative overview of the molecular and biochemical modulators governing synaptic plasticity and their disruption in AD. We discuss how the collective impairment of Aβ aggregation, tau pathology, calcium imbalance, oxidative stress, and neuroinflammation affects dendritic spine morphology and synaptic connectivity. Particular attention is given to neurotrophins such as brain-derived neurotrophic factor and TrkB signaling, hormonal influences, likewise glucocorticoids, estrogens, testosterone, endocannabinoid pathways, lipid and cholesterol regulators like ApoE and lipid rafts, and epigenetic mechanisms that modulate synaptic resilience. We further evaluate the therapeutic potential of pharmacological agents, including cholinesterase inhibitors, NMDA receptor modulators, and multi-target directed ligands alongside nutraceuticals such as resveratrol, curcumin, omega-3 fatty acids, Withania somnifera, and Bacopa monnieri. Emerging technologies, including iPSC-derived neuronal models, optogenetics, and advanced neuroimaging biomarkers like SV2A PET, cerebrospinal fluid/plasma neurogranin, are also highlighted for their role in elucidating and monitoring synaptic integrity. Ultimately, targeting the biochemical modulators of synaptic plasticity offers a promising avenue for AD therapy, especially through combinatorial and precision-medicine strategies aimed at restoring synaptic function and cognitive performance.

The Role of Neuroinflammation in Alzheimer's Disease: Molecular Mechanisms and Emerging Therapeutic Approaches

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder traditionally characterized by amyloid-beta (Aβ) accumulation, tau pathology, synaptic dysfunction, and neuronal loss. Increasing evidence indicates that neuroinflammation is not merely a secondary consequence of neurodegeneration but an important component of AD pathogenesis. This review examines the molecular and cellular mechanisms through which neuroinflammation contributes to the progression of AD, with particular emphasis on microglial activation, TREM2 and soluble TREM2 (sTREM2) signaling, NLRP3 inflammasome activation, astrocyte–microglia interactions, and blood–brain barrier dysfunction. The review further evaluates emerging therapeutic strategies aimed at modulating these pathways, including NLRP3 inhibition, TREM2/sTREM2-targeted approaches, restoration of glial homeostasis, cytokine modulation, and pro-resolving strategies. Current evidence suggests that inflammatory responses may exert both protective and detrimental effects depending on disease stage, duration, and cellular context. Consequently, broad suppression of neuroinflammation may be insufficient and potentially counterproductive. Future therapeutic development may benefit from precision immunomodulation guided by disease-stage-specific biomarkers and molecular profiling. Understanding the complex interactions between neuroinflammation, pathological protein accumulation, glial dysfunction, and neurovascular abnormalities may therefore provide new opportunities for developing disease-modifying approaches to Alzheimer’s disease.

Roles of Microglia and Astrocytes in Neuroinflammation of Alzheimer's Disease: From Mechanisms to Therapeutics

Alzheimer's disease (AD) is one of the most common types of neurodegenerative diseases. Its pathogenesis involves the interaction of multiple factors, including β-amyloid deposition, excessive tau protein phosphorylation, neuroinflammation, and synaptic dysfunction. Among these, neuroinflammation is widely recognized as a key factor driving the onset and progression of AD. As the two main types of glial cells in the central nervous system, microglia and astrocytes play central roles in the regulation of neuroinflammation. This paper systematically reviews the structural characteristics and functional states of microglia and astrocytes in AD-related neuroinflammation, as well as their interactions with Aβ and tau pathologies. Both types of glial cells exhibit a bidirectional transition from a protective to a damaging phenotype. In the early stage, they exert neuroprotective effects by phagocytosing and clearing abnormal proteins and releasing neurotrophic factors. Under sustained inflammatory stimulation, both gradually shift to a pro-inflammatory activated state, releasing large amounts of inflammatory factors, disrupting the blood-brain barrier and glymphatic system, and abnormally phagocytosing synaptic structures, forming a vicious cycle in which pathological protein deposition and excessive glial cell activation mutually exacerbate each other. More importantly, the two types of glial cells interact through various pathways such as cytokines, complement pathways, and signaling molecules, jointly amplifying the inflammatory cascade. This paper also summarizes therapeutic strategies for drugs targeting these two glial cells, including cholinesterase inhibitors, NMDA receptor antagonists, non-steroidal anti-inflammatory drugs, and biological agents targeting Aβ and tau proteins. In conclusion, functional abnormalities and interactive disorders of microglia and astrocytes are the core driving factors of AD neuroinflammation. An in-depth understanding of the molecular mechanisms underlying their interaction will provide a new breakthrough for shifting AD treatment from symptomatic management to etiological eradication.

Astrocytes orchestrate neuroprotection and pathogenesis via bidirectional neuronal interactions in Parkinson’s disease

Microglia-mediated neuroinflammation in Alzheimer’s disease: mechanisms and emerging therapeutic targets

A “cellular state–pathological network–therapeutic window” framework is proposed and the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA–cGAS–STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia–tau feedback are systematically discussed.

Cognitive dysfunction in Parkinson's disease: Hippocampal vulnerability and redox-driven mechanisms.

Cognitive dysfunction is one of the most disabling non-motor manifestations of Parkinson's disease (PD), progressing from mild cognitive impairment to Parkinson's disease dementia. Although multiple pathological processes have been individually implicated, the mechanisms linking neurotransmitter deficits, proteinopathies, circuit vulnerability, and neurodegeneration remain insufficiently integrated. Here, we synthesize current evidence on the pathophysiology of cognitive impairment in PD, emphasizing the convergence of dopaminergic, cholinergic, noradrenergic and serotonergic dysfunction with α-synuclein, tau and amyloid-β pathology. We highlight the hippocampus – particularly the CA2 subregion – as a critical anatomical hub connecting synaptic dysfunction, memory impairment, and dementia progression. Accumulating evidence identifies oxidative stress and neuroinflammation as central drivers across these pathological domains. Among endogenous sources of reactive oxygen species, NADPH oxidases (NOX), especially Nox4, emerge as key regulators of redox imbalance, protein aggregation and glial–neuronal interactions. Increased Nox4 activity correlates with hippocampal damage and cognitive decline, whereas experimental inhibition of Nox4 preserves synaptic integrity and improves memory performance in preclinical models. By integrating molecular, cellular and systems-level findings, this review positions redox dysregulation – and NOX-dependent signaling in particular – as a unifying mechanism underlying cognitive decline in PD, and discusses emerging therapeutic strategies targeting redox pathways, highlighting NOX modulation as a promising approach to modify the course of Parkinson's disease-associated cognitive impairment.