Transcription factor EB improves Alzheimer’s disease via the autophagy-lysosome pathway

Abstract

BACKGROUND: Studies have confirmed that transcription factor EB and its dependent autophagy-lysosome pathway play a role in the development of various neurodegenerative diseases, including Alzheimer’s disease. OBJECTIVE: To summarize the role of transcription factor EB-mediated autophagy-lysosome pathway in Alzheimer’s disease. METHODS: Electronic databases including PubMed, Web of Science, Cochrane Library, CNKI, WanFang Medical Network, and VIP were searched. The search period was from database inception to January 2025. The search terms were “Alzheimer Disease, AD, Transcription Factor EB, TFEB, Autophagy-lysosome Pathway, Autophagy, Lysosomes, Amyloid beta, Aβ, Tau, Tau protein” in English as well as “Alzheimer’s disease, transcription factor EB, autophagic lysosomes, autophagy, lysosomes, β-amyloid, Tau” in Chinese. Additionally, the references of relevant reviews and grey literature were manually supplemented. A total of 100 articles were finally included for review. RESULTS AND CONCLUSION: Amyloid-β deposition and Tau protein phosphorylation are the key pathological features of Alzheimer’s disease. Abnormalities in the autophagy-lysosome pathway promote the formation of neurotoxic protein aggregates such as amyloid-β and Tau, leading to the clinical manifestations of Alzheimer’s disease characterized by cognitive dysfunction and behavioral abnormalities. Transcription factor EB is a key regulator of the autophagy-lysosome pathway, controlling the transcription of many autophagy-related genes and lysosomal biogenesis. After entering the nucleus, transcription factor EB upregulates the expression of autophagy-lysosome pathway-related genes, significantly increasing the clearance rate of amyloid-β and Tau and significantly reducing neuronal toxicity. Therefore, increasing attention focuses on targeting transcription factor EB to influence autophagy-lysosome biological activity, thereby improving Alzheimer’s disease pathology and behavioral deficits. For example, both pharmacological and non-pharmacological interventions can activate transcription factor EB, reducing amyloid-β deposition and Tau phosphorylation, and improving cognitive function in Alzheimer’s disease. However, sustained activation of transcription factor EB may pose risks such as lysosomal storage disorders, and current intracranial delivery systems have insufficient targeting efficiency. Future development of pathological microenvironment-responsive carriers and combination therapies is needed to achieve precise intervention.

1. Introduction

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder clinically characterized by progressive cognitive decline, psychiatric symptoms, and impaired social functioning. Despite the rising prevalence, the precise pathophysiological mechanisms remain incompletely understood. However, multiple studies have established that the brain pathology of AD involves diffuse cerebral atrophy, with microscopic hallmarks including extracellular deposition of β-amyloid (Aβ) plaques, intraneuronal neurofibrillary tangles composed of hyperphosphorylated Tau protein, and neuronal loss in specific brain regions [1].

The autophagy-lysosome pathway (ALP) serves as the cell’s “cleanup crew,” maintaining cellular homeostasis by degrading aggregated proteins, damaged organelles, and invading pathogens. This pathway is complex and regulated by multiple signaling cascades under various stress conditions, among which transcription factor EB (TFEB) plays a pivotal role. Numerous studies have confirmed that TFEB and its dependent ALP are involved in the pathogenesis of various neurodegenerative diseases, including AD. This review aims to summarize the role of TFEB-mediated ALP in AD, focusing on its regulatory mechanisms and therapeutic potential.