Autophagy is an important cellular self-digestion and recycling pathway that helps in maintaining cellular homeostasis. Dysregulation at various steps of the autophagic and endolysosomal pathway has been reported in several neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington disease (HD) and is cited as a critically important feature for central nervous system (CNS) proteostasis. Recently, another molecular target, namely transcription factor EB (TFEB) has been explored globally to treat neurodegenerative disorders. This TFEB, is a key regulator of autophagy and lysosomal biogenesis pathway. Multiple research studies suggested therapeutic potential by targeting TFEB to treat human diseases involving autophagy-lysosomal dysfunction, especially neurodegenerative disorders. A common observation involving all neurodegenerative disorders is their poor efficacy in clearing and recycle toxic aggregated proteins and damaged cellular organelles due to impairment in the autophagy pathway. This dysfunction in autophagy characterized by the accumulation of toxic protein aggregates leads to a progressive loss in structural integrity/functionality of neurons and may even result in neuronal death. In recent years TFEB, a key regulator of autophagy and lysosomal biogenesis, has received considerable attention. It has emerged as a potential therapeutic target in numerous neurodegenerative disorders like AD and PD. In various neurobiology studies involving animal models, TFEB has been found to ameliorate neurotoxicity and rescue neurodegeneration. Since TFEB is a master transcriptional regulator of autophagy and lysosomal biogenesis pathway and plays a crucial role in defining autophagy activation. Studies have been done to understand the mechanisms for TFEB dysfunction, which may yield insights into how TFEB might be targeted and used for the therapeutic strategy to develop a treatment process with extensive application to neurodegenerative disorders. In this review, we explore the role of different transcription factor-based targeted therapy by some natural compounds for AD and PD with special emphasis on TFEB.

Selective permeability of the blood–brain barrier limits effective treatment of neurodegenerative disorders. In the present study, brain-targeted lipid-coated mesoporous silica nanoparticles (MSNs) containing berberine (BBR) were synthesized for the effective treatment of Alzheimer’s disease (AD). The study involved synthesis of Mobil Composition of Matter-41 (MCM-41) mesoporous silica nanoparticles (MSNs), BBR loading, and lipid coating of MSNs (MSNs-BBR-L) and in vitro and in vivo characterization of MSNs-BBR-L. The liposomes (for lipid coating) were prepared by the thin-film hydration method. Transmission electron microscopy (TEM) images indicated 5 nm thickness of the lipid coating. Dynamic light scattering (DLS) and TEM results confirmed that the size of synthesized MSNs-BBR-L was in the range of 80–100 nm. The X-ray diffraction (XRD) pattern demonstrated retention of the ordered structure of BBR after encapsulation and lipid coating. Fourier transform infrared (FTIR) spectrum confirmed the formation of a lipid coat over the MSN particles. MSNs-BBR-L displayed significantly (p < 0.05) higher acetylcholine esterase (AChE) inhibitory activity. The study confirmed significant (p < 0.05) amyloid fibrillation inhibition and decreased the malondialdehyde (MDA) level by MSNs-BBR-L. Pure BBR- and MSNs-BBR-L-treated AD animals showed a significant decrease in the BACE-1 level compared to scopolamine-intoxicated mice. Eight times higher area under the curve for MSNs-BBR-L (2400 ± 27.44 ng h/mL) was recorded compared to the pure BBR (295.5 ± 0.755 ng h/mL). Overall, these results highlight the utility of MSNs-BBR-L as promising drug delivery vehicles for brain delivery of drugs.

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