title: Inhibition of serine palmitoyltransferase reduces Aβ and tau hyperphosphorylation in a murine model: a safe therapeutic strategy for Alzheimer's disease.
abstract: The contribution of the autosomal dominant mutations to the etiology of familial Alzheimer's disease (AD) is well characterized. However, the molecular mechanisms contributing to sporadic AD are less well understood. Increased ceramide levels have been evident in AD patients. We previously reported that increased ceramide levels, regulated by increased serine palmitoyltransferase (SPT), directly mediate amyloid β (Aβ) levels. Therefore, we inhibited SPT in an AD mouse model (TgCRND8) through subcutaneous administration of L-cylcoserine. The cortical Aβ₄₂ and hyperphosphorylated tau levels were down-regulated with the inhibition of SPT/ceramide. Positive correlations were observed among cortical SPT, ceramide, and Aβ₄₂ levels. With no evident toxic effects observed, inhibition of SPT could be a safe therapeutic strategy to ameliorate the AD pathology. We previously observed that miR-137, -181c, -9, and 29a/b post-transcriptionally regulate SPT levels, and the corresponding miRNA levels in the blood sera are potential diagnostic biomarkers for AD. Here, we observe a negative correlation between cortical Aβ₄₂ and sera Aβ₄₂, and a positive correlation between cortical miRNA levels and sera miRNA levels suggesting their potential as noninvasive diagnostic biomarkers.
authors.affiliation: Genetics Program, Michigan State University, East Lansing, MI 48824, USA. geekiyanage.donahirosha@mayo.edu
authors.forename: Hirosha
authors.initials: H
authors.lastname: Geekiyanage
authors.forename: Aditi
authors.initials: A
authors.lastname: Upadhye
authors.forename: Christina
authors.initials: C
authors.lastname: Chan
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002518:Ceramides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000097:blood / Q000378:metabolism / Q000502:physiology / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism; D010766:Phosphorylation; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D002518:Ceramides; D035683:MicroRNAs; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D051102:Serine C-Palmitoyltransferase