Here’s a PDF of my poster for the EMBO autophagy conference in May 2013.  And here’s the abstract.

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,^[1] and 2) neuronal insulin resistance, characterized by increased amyloid-β (Aβ) production in autophagosomes and reduced neuronal internalization of extracellular Aβ oligomers.^[2]

Translocation of transcription factor EB (TFEB) from cytosol to nucleus increases transcription of 291 genes and thereby induces autophagy,^[3] lysosomal biogenesis, acidification, and proteolysis.^[4]

Phosphorylation of TFEB by mammalian target of rapamycin complex 1 (mTORC1) and by glycogen synthase kinase 3 (GSK3)^[5] inhibits TFEB nuclear translocation.

GSK3 inhibition in transgenic AD mice increases acidification of lysosomes, reduces Aβ deposits, and ameliorates cognitive deficits.^[6]

Why very low protein intake?  mTORC1 phosphorylation of TFEB is inhibited by amino acid starvation, even in the presence of strong insulin signaling.^[7]  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^[8] and presumably therefore reduces GSK3’s phosphorylation of TFEB.  Combined with mTORC1 inhibition, enhanced insulin signaling should thereby promote TFEB nuclear translocation.

Continue reading →