Protective effects of reduced dynamin-related protein 1 against amyloid beta-induced mitochondrial dysfunction and synaptic damage in Alzheimer's disease

Maria Manczak, Ramesh Kandimalla, David Fry, Hiromi Sesaki, P (Hemachandra) Reddy

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

The purpose of our study was to understand the protective effects of reduced expression of dynamin-related protein (Drp1) against amyloid beta (Aβ) induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD) progression and pathogenesis. Our recent molecular and biochemical studies revealed that impaired mitochondrial dynamics-increased mitochondrial fragmentation and decreased fusion-in neurons from autopsy brains of AD patients and from transgenic AD mice and neurons expressing Aβ, suggesting that Aβ causes mitochondrial fragmentation in AD. Further, our recent coimmunoprecipitation and immunostaining analysis revealed that the mitochondrial fission protein Drp1 interacted with Aβ, and this interaction increased as AD progressed. Based on these findings, we hypothesize that a partial deficiency of Drp1 inhibits Drp1-Aβ interactions and protects Aβ-induced mitochondrial and synaptic toxicities, and maintains mitochondrial dynamics and neuronal function in AD neurons. We crossed Drp1+/- mice with APP transgenic mice (Tg2576 line) and created double mutant (APPXDrp1+/-) mice. Using real-time RT-PCR and immunoblotting analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics, mitochondrial biogenesis and synapses from 6-month-old Drp1+/-, APP, APPXDrp1+/- and wild-type (WT) mice. Using biochemical methods, we also studied mitochondrial function and measured soluble Aβ in brain tissues from all lines of mice in our study. Decreased mRNA expressions and protein levels of Drp1 and Fis1 (fission) and CypD (matrix) genes, and increased levels of Mfn1, Mfn2 and Opa1 (fusion), Nrf1, Nrf2, PGC1a, TFAM (biogenesis) and synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin (synaptic) were found in 6-month-old APPXDrp1+/- mice relative to APP mice. Mitochondrial functional assays revealed that mitochondrial dysfunction is reduced in APPXDrp1+/- mice relative to APP mice, suggesting that reduced Drp1enhances mitochondrial function in AD neurons. Sandwich ELISA assay revealed that soluble Aβ levels were significantly reduced in APPXDrp1+/- mice relative to APP mice, indicating that reduced Drp1 decreases soluble Aβ production in AD progression. These findings suggest that a partial reduction of Drp1 reduces Aβ production, reduces mitochondrial dysfunction, and maintains mitochondrial dynamics, enhances mitochondrial biogenesis and synaptic activity in APP mice. These findings may have implications for the development of Drp1 based therapeutics for AD patients.

Original languageEnglish (US)
Pages (from-to)5148-5166
Number of pages19
JournalHuman Molecular Genetics
Volume25
Issue number23
DOIs
StatePublished - 2016
Externally publishedYes

Fingerprint

Dynamins
Amyloid
Alzheimer Disease
Mitochondrial Dynamics
Proteins
Neurons
Organelle Biogenesis
Vesicle-Associated Membrane Protein 1
Disease Progression
Neurogranin
Synapsins
Messenger RNA
Synaptophysin
Mitochondrial Proteins
Brain Diseases
Immunoblotting
Synapses
Transgenic Mice
Real-Time Polymerase Chain Reaction
Autopsy

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Protective effects of reduced dynamin-related protein 1 against amyloid beta-induced mitochondrial dysfunction and synaptic damage in Alzheimer's disease. / Manczak, Maria; Kandimalla, Ramesh; Fry, David; Sesaki, Hiromi; Reddy, P (Hemachandra).

In: Human Molecular Genetics, Vol. 25, No. 23, 2016, p. 5148-5166.

Research output: Contribution to journalArticle

Manczak, Maria ; Kandimalla, Ramesh ; Fry, David ; Sesaki, Hiromi ; Reddy, P (Hemachandra). / Protective effects of reduced dynamin-related protein 1 against amyloid beta-induced mitochondrial dysfunction and synaptic damage in Alzheimer's disease. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 23. pp. 5148-5166.
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