Here’s the poster’s text:
An autophagic role in Alzheimer’s disease for intermittent dietary periods of very low-protein, high-carbohydrate intake
Hypothesis: Intermittent periods of very low-protein, high-carbohydrate dietary intake may enhance autolysosomal proteolysis in Alzheimer’s disease (AD) by increasing activity of transcription factor EB (TFEB).
Background: AD is characterized by 1) activation of neuronal autophagy with defective autolysosomal degradation, and 2) neuronal insulin resistance, characterized by increased amyloid-β (Aβ) production in autophagosomes and reduced neuronal internalization of extracellular Aβ oligomers.
Translocation of transcription factor EB (TFEB) from cytosol to nucleus increases transcription of 291 genes and thereby induces autophagy, lysosomal biogenesis, acidification, and proteolysis.
Phosphorylation of TFEB by mammalian target of rapamycin complex 1 (mTORC1) and by glycogen synthase kinase 3 (GSK3) inhibits TFEB nuclear translocation.
GSK3 inhibition in transgenic AD mice increases acidification of lysosomes, reduces Aβ deposits, and ameliorates cognitive deficits.
Why very low protein intake? mTORC1 phosphorylation of TFEB is inhibited by amino acid starvation, even in the presence of strong insulin signaling. Very low protein intake, combined with GSK3 inhibition, is therefore expected to promote TFEB nuclear translocation.
Why high carbohydrate intake? High carbohydrate intake stimulates secretion of insulin, which inhibits GSK3 and presumably therefore reduces GSK3’s phosphorylation of TFEB. Combined with mTORC1 inhibition, enhanced insulin signaling should thereby promote TFEB nuclear translocation.
This hypothesis awaits testing, e.g., in a transgenic AD mouse model.
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