Jul 2026· Neuro-degenerative diseases· pp. 1-16· 0 citations
Medicine
TL;DR
Targeting autophagy offers a promising and potentially safe avenue for slowing AD progression and should prioritize the development of selective autophagy modulators and personalized treatment strategies to restore autophagic flux and enhance clinical outcomes in patients with AD.
Abstract
Abstract Background Alzheimer’s disease (AD) is an incurable progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain. Recent findings have identified dysregulation of autophagy, a cellular mechanism for degradation and recycling, as a crucial contributor to the pathogenesis of AD. This narrative review examines the role of autophagy in the metabolism of Aβ and tau and evaluates current therapeutic strategies aimed at modulating autophagic pathways. Summary Autophagy is governed by the key molecular regulators mammalian target of rapamycin, adenosine monophosphate-activated protein kinase, Beclin-1, and transcription factor EB, which collectively control the clearance of protein recycling, including aggregates, inside cells. Pharmacological agents such as rapamycin, resveratrol, and trehalose, alongside sigma-1 receptor agonists and gene therapy approaches, have demonstrated potential in modulating autophagy in preclinical and clinical studies. Despite these advances, significant challenges persist, namely, neuronal heterogeneity, optimal timing for therapeutic intervention, and the absence of reliable biomarkers to monitor autophagic activity and treatment efficacy. Key Messages Targeting autophagy offers a promising and potentially safe avenue for slowing AD progression. Future investigations should prioritize the development of selective autophagy modulators and personalized treatment strategies to restore autophagic flux and enhance clinical outcomes in patients with AD.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid‐β (Aβ) plaques and tau (τ) ‐related neurofibrillary tangles, often exacerbated by dysfunctional cellular clearance mechanisms. This manuscript explores the pivotal role of autophagy impairment in AD pathogenesis, with a specific focus on the AMPK/mTOR signaling axis as a primary regulatory pathway. Findings revealed that while mTOR overactivation suppresses autophagic flux and promotes the buildup of toxic protein aggregates, the activation of AMPK serves to restore homeostatic degradation processes. The review highlights that various pharmacological agent including rapamycin, metformin, trehalose, and curcumin, as well as repurposed drugs like lithium and statins can effectively enhance autophagy to ameliorate cognitive decline and neuroinflammation. Furthermore, herbal formulations such as Danggui Shaoyao San and phytoconstituents like Icariin demonstrate significant neuroprotective potential by modulating these same molecular pathways. Targeting autophagy represents a translationally viable approach for combating AD progression, with drug repurposing offering a time‐efficient and cost‐effective strategy. To advance these findings, future research should prioritize large‐scale clinical trials to validate the efficacy of autophagy‐inducing agents in human subjects. Additionally, investigating synergistic combinations of traditional bioactives with synthetic drugs and utilizing innovative delivery systems, such as intranasal nanotechnology‐based platforms to bypass the blood‐brain barrier, represents a promising frontier for developing effective, multi‐targeted treatments against AD.
Ayush Dubey, Ayush Chaurasia, Zeeshan Ansari et al.· Drug development research (P...· 0 citations
Alzheimer's disease (AD) is the leading cause of dementia, yet current therapies provide limited clinical benefit. Neuroinflammation, as an early and sustained driver of AD, places the NLRP3 inflammasome at the center of pathological and therapeutic focus. In this review, we synthesize recent advances in the structure, assembly, and activation of the NLRP3 inflammasome, and evaluate its contribution to AD using evidence from human brain tissues, cerebrospinal fluid, and diverse AD animal models. Available data consistently support aberrant NLRP3 activation in AD brain, where it is closely associated with amyloid-β (Aβ) deposition, tau pathology, glial reactivity, and cognitive decline. We further discuss the cell-type-specific roles of microglia and astrocytes, highlighting microglia as the principal effector cells in inflammasome-associated pathology. Mechanistically, Aβ and tau converge on NLRP3 activation through interconnected pathways involving K+ efflux, lysosomal rupture, mitochondrial dysfunction, and impaired autophagy. Downstream IL-1β, IL-18, and gasdermin D amplify neuroinflammation and neuronal injury. We summarize emerging therapeutic strategies directly targeting its core components or downstream effectors, as well as anti-AD agents with indirect NLRP3 modulation including endogenous molecules, repurposed drugs, and natural products. Collectively, this review regards NLRP3 inflammasome as a critical inflammatory hub and a promising target for disease-modifying therapy in AD, and provide useful perspectives on AD pathogenesis and inform the development of more rational therapeutic strategies.
Wenwen Lian, Fulin Zhou, Zhuohang Tong et al.· Ageing Research Reviews· 0 citations
Overall, this review makes a case for integrative, pathway-based therapeutic models, and multiple approaches may facilitate for drug development, biomarker identification and patient management in Alzheimer's disease.
Alzheimer’s disease (AD), the most prevalent cause of dementia, lacks definitive cures despite decades of research focused on amyloid-beta (Aβ) and tau pathologies. Emerging evidence positions mitochondrial dysfunction not merely as a downstream consequence, but as the epicenter linking aging, metabolic failure, and neuroinflammation in AD pathogenesis. This study synthesizes the latest advances in mitochondrial-targeted therapies, framing them within a “Mitochondrial Ecological Restoration” perspective. I analyze the molecular mechanisms by which mitochondrial-targeted therapies modulate oxidative stress, mitochondrial dynamics, mitophagy and neuroinflammation, and evaluate their translational potential. Accumulating evidence indicates that strategies ranging from antioxidants (e.g., MitoQ) to mitophagy enhancement (e.g., Spautin-1) and biogenesis activation (e.g., PGC-1α Activator) have demonstrated efficacy in preclinical models. These interventions theoretically interrupt the pathological cycle between proteotoxicity and bioenergetic crisis. While challenges in blood-brain barrier (BBB) penetration and target specificity persist, the field is shifting from single-target scavenging to combinatorial ecosystem repair. Future success will require precise delivery systems, early biomarkers, and a paradigm shift toward treating the neuron as a metabolic ecosystem, though substantial translational challenges remain.
Dan-Dan Song· Frontiers in Cell and Develo...· 0 citations
Alzheimer's disease (AD), as the leading cause of dementia, poses an increasingly severe socioeconomic burden in the context of global ageing. Traditionally defined by amyloid-β and tau pathology, it's increasingly recognized as a systems disorder in which impaired glucose metabolism, mitochondrial dysfunction, and neuroinflammation interact across neural cell types and disease stages. However, the interaction among these three mechanisms, their role in promoting the classical pathology of AD, and their verification in major neural cell types remains unclear. This review summarizes the alterations in glucose metabolism and mitochondrial metabolism in neurons, astrocytes and microglia in AD and their relationship with neuroinflammation, while also discussing some unaddressed questions, outlining therapeutic strategies, and future promising directions. Biomarkers that reflect disease stage and pathological status, multitarget therapeutic strategies, individualized precision medicine, and the integration of pharmacological with non-pharmacological interventions represent particularly promising directions for the future.
Yinuo Lei, Liyang Liu, Yi Tang· Ageing Research Reviews· 0 citations
Alzheimer’s disease (AD), a progressive neurodegenerative disorder, remains a major global health challenge owing to its complex pathogenesis and the presence of the blood-brain barrier (BBB), which substantially limits the delivery of effective therapeutics to the brain. Extracellular vesicles (EVs), which exhibit favorable biocompatibility, low immunogenicity, and an intrinsic capacity to cross the BBB, have emerged as promising therapeutic agents and delivery platforms for AD. This review focuses on the therapeutic potential of EV-based interventions in AD and summarizes recent advances in EV-mediated modulation of AD-related pathological processes, including amyloid-β (Aβ) clearance, tau protein regulation, neuroinflammation suppression, oxidative stress attenuation, and synaptic repair. Although EV-based therapies offer notable advantages, such as targeted BBB penetration and reduced immunogenic responses, their clinical translation remains constrained by safety concerns, including off-target effects, dose-dependent toxicity, and potential disturbances in neuroplasticity. In addition, this review discusses EV engineering strategies aimed at regulating the gut-brain axis (GBA), enhancing brain targeting, and advancing clinical translation. EV-based therapeutic interventions should therefore be developed within a safety-oriented framework supported by rigorous short- and long-term toxicological evaluation. Overall, this review highlights the therapeutic promise of EVs for AD while underscoring the need for rational engineering, standardized characterization, and safety-centered translational strategies to ensure clinical feasibility.
Ailin Wu, Yan Zeng, Yilin Huang et al.· Extracellular Vesicles and C...· 0 citations
