Mitochondria-targeted small molecule SS31: A potential candidate for the treatment of Alzheimer's disease

P (Hemachandra) Reddy, Maria Manczak, Ramesh Kandimalla

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

The objective of our study was to better understand the protective effects of the mitochondria-targeted tetra-peptide SS31 against amyloid beta (Ab)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD) progression. Using intraperitoneal injections, we administered SS31 to an AD mouse model (APP) over a period of 6 weeks, beginning when the APP mice were 12 months of age. We studied their cortical tissues after SS31 treatment and determined that SS31 crosses the blood brain barrier and reaches mitochondrial sites of free radical production. We also determined: (1) plasma and brain levels of SS31, (2) mRNA levels and levels of mitochondrial dynamics, biogenesis proteins and synaptic proteins, (3) soluble Ab levels and immunoreactivity of mutant APP and Ab levels and (4) mitochondrial function by measuring H2O2, lipid peroxidation, cytochrome c oxidase activity and mitochondrial ATP. We found reduced mRNA expression and reduced protein levels of fission genes, and increased levels of mitochondrial fusion, biogenesis and synaptic genes in SS31-treated APP mice relative to SS31-untreated APP mice. Immunofluorescence analysis revealed reduced full-length mutant APP and soluble/insoluble Ab levels in the SS31-treated APP mice. Sandwich ELISA assays revealed significantly reduced soluble Ab levels in the SS31-treated APP mice relative to the untreated APP mice. Mitochondrial function was maintained in the SS31-treated APP mice over the 6 weeks of SS31 treatment compared with mitochondrial function in the untreated APP mice. Our findings indicate that SS31 treatment reduces Ab production, reduces mitochondrial dysfunction, maintains mitochondrial dynamics and enhances mitochondrial biogenesis and synaptic activity in APP mice; and that SS31 may confer protective effects against mitochondrial and synaptic toxicities in APP transgenic mice.

Original languageEnglish (US)
Article numberddx052
Pages (from-to)1483-1496
Number of pages14
JournalHuman Molecular Genetics
Volume26
Issue number8
DOIs
StatePublished - Apr 15 2017
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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