Mitochondrial Bioenergetics Is Altered in Fibroblasts from Patients with Sporadic Alzheimer's Disease.

María J Pérez,Cesar Osorio-Fuentealba,Daniela P Ponce,Rodrigo A Quintanilla,Maria I Behrens

doi:10.3389/fnins.2017.00553

Abstract

The identification of an early biomarker to diagnose Alzheimer's disease (AD) remains a challenge. Neuropathological studies in animal and AD patients have shown that mitochondrial dysfunction is a hallmark of the development of the disease. Current studies suggest the use of peripheral tissues, like skin fibroblasts as a possibility to detect the early pathological alterations present in the AD brain. In this context, we studied mitochondrial function properties (bioenergetics and morphology) in cultured fibroblasts obtained from AD, aged-match and young healthy patients. We observed that AD fibroblasts presented a significant reduction in mitochondrial length with important changes in the expression of proteins that control mitochondrial fusion. Moreover, AD fibroblasts showed a distinct alteration in proteolytic processing of OPA1, a master regulator of mitochondrial fusion, compared to control fibroblasts. Complementary to these changes AD fibroblasts showed a dysfunctional mitochondrial bioenergetics profile that differentiates these cells from aged-matched and young patient fibroblasts. Our findings suggest that the human skin fibroblasts obtained from AD patients could replicate mitochondrial impairment observed in the AD brain. These promising observations suggest that the analysis of mitochondrial bioenergetics could represent a promising strategy to develop new diagnostic methods in peripheral tissues of AD patients.

Highlights

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases worldwide and is considered the leading cause of dementia in the world’s adult population (Hirtz et al, 2007)
Mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1) are proteins required for controlling mitochondrial fusion, and fission depends mainly on dynaminrelated protein 1 (DRP1) activity (Wang et al, 2009a; Friedman et al, 2011; Murley et al, 2013)
We found that AD fibroblasts showed a specific pattern of OPA1 processing compared to control patients (Figure 2D), which consisted of a significant decrease in L1, S3, and S4 and a prominent increase in S5 form (Figure 2G)

Summary

Introduction

AD is one of the most common neurodegenerative diseases worldwide and is considered the leading cause of dementia in the world’s adult population (Hirtz et al, 2007). AD diagnosis is based on neuropsychological surveys and in the exclusion of other age-related dementias in consultant patients (Lanfranco et al, 2012). Analysis of this data has determined three stages of AD progression: preclinical AD, mild cognitive impairment type Alzheimer’s, and Alzheimer’s type dementia (Lanfranco et al, 2012). The confirmation of AD is only possible during the patient’s autopsy observing the characteristic pathological brain lesions (Khan and Alkon, 2015)

Methods

Results

Discussion

Conclusion