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P2‐106: Brain and Blood Metabolite Signatures of Pathology and Progression in Alzheimer’s Disease
Author(s) -
Thambisetty Madhav,
Varma Sudhir,
Casanova Ramon,
An Yang,
Pletnikova Olga,
O'Brien Richard,
Troncoso Juan C.,
Quigley Cristina Legido
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.1312
Subject(s) - medicine , asymptomatic , alzheimer's disease , disease , longitudinal study , pathology , atrophy , metabolite , cognition , neuroimaging , physiology , oncology , neuroscience , psychology , psychiatry
their correct functioning, proteins require folding, which needs ATP generated by mitochondria to provide energy for chaperones, e.g., HSP70, to assist that folding. Stress causes accumulation of unfolded proteins, provoking the “Unfolded Protein Response” at the endoplasmic reticulum. Dysfunctional mitochondria producing insufficient ATP may result in improper protein folding leading, crucially, to amyloid/oligomers. Dysfunctional mitochondria require elimination by mitophagy; also needed is biogenesis of new organelles having normal function. Mitophagy, i.e., autophagocytic disposal of damaged mitochondria, commences by engulfing damaged mitochondria into an autophagocytic vacuole (AV), after which comes a series of intermediate vacuoles and ultimately fusion with a lysosome for enzymatic digestion of contents. AD brains showed 20-fold more AVs than control brains (1); those AVs would include impaired mitochondria. Methods: Review of relevant literature in AD regarding mitophagic elimination of dysfunctional mitochondria and biogenesis of new, functional, mitochondria. (Full references will be provided). Results: Mitophagic enhancement. Inositol inhibits mitophagy; lithium depletes inositol (by inhibiting IMP3) thus enhancing mitophagy [by an uncertain molecular mechanism (2)]. Mitochondrial depletion stimulates mitochondrial biogenesis. Other drugs that enhance mitochondrial biogenesis include erythropoietin and pioglitazone. Erythropoietin activates eNOS, causing production of nitric oxide (NO), which triggers transcription of genes involved in mitochondrial biogenesis (3). Thiazolidinediones, e.g., pioglitazone, induce mitochondrial biogenesis by increasing expression of PPAR-1a-coactivator, the principle regulator of mitochondrial biogenesis. (4). Treatment using concurrent combinations having different targets is more effective than sequentially using single agents. A clinical trial would test the hypothesis that a combination of lithium, erythropoietin, and pioglitazone, might impede the progression of MCI to AD, or of early to more advanced AD. Conclusions: Dysfunctional mitochondria underlie AD andmay be cleared, by combining lithium, erythropoietin, and pioglitazone to enhance mitophagy, which then stimulates birth of new organelles by enhancing mitochondrial biogenesis. Nixon, J Cell Sci 2007;120:4081-4091. Sarkar, J Cell Biol 2011;101:514-519. Burger, Cardiovasc Res 2006;72:51-59. Gosh, Mol Pharmacol 2007;71:1695-1702.