Alzheimer’s at EMBO 2013: dietary treatment and prevention through autophagy

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.

This hypothesis awaits testing, e.g., in a transgenic AD mouse model.


[1] Nixon RA, Yang DS. Autophagy failure in Alzheimer’s disease—locating the primary defect. Neurobiology of Disease (2011) 43(1): 38-45.

[2] Talbot K, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. (2012) 122(4): 1316–1338.

[3] Settembre C, et al. TFEB Links Autophagy to Lysosomal Biogenesis. Science (2011) 332(6036): 1429-1433.

[4] Sardiello M, et al. A Gene Network Regulating Lysosomal Biogenesis and Function. Science (2009) 325(5939): 473-477.

[5] Parr C, et al. GSK3 inhibition promotes lysosomal biogenesis and the autophagic degradation of the Amyloid-β Precursor Protein. Mol. Cell. Biol. (2012) 32(21): 4410-4418.

[6] Avrahami L, et al. Inhibition of GSK-3 Ameliorates beta-Amyloid(A-beta) Pathology and Restores Lysosomal Acidification and mTOR Activity in the Alzheimer’s Disease Mouse Model. In vivo and In vitro Studies.  J Biol Chem (2012) Nov 15.

[7] Settembre C, et al.  A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. The EMBO Journal (2012) 31, 1095-1108.

[8] Collino M, et al. Insulin Reduces Cerebral Ischemia/Reperfusion Injury in the Hippocampus of Diabetic Rats. A Role for Glycogen Synthase Kinase-3β.  Diabetes (2009) 58(1): 235-242.

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