Deconstructing mitochondrial dysfunction in Alzheimer disease

Abstract

There is mounting evidence showing that mitochondrial damage plays an important role in Alzheimer disease. Increased oxygen species generation and deficient mitochondrial dynamic balance have been suggested to be the reason as well as the consequence of Alzheimer-related pathology. Mitochondrial damage has been related to amyloid-beta or tau pathology or to the presence of specific presenilin-1 mutations. The contribution of these factors to mitochondrial dysfunction is reviewed in this paper. Due to the relevance of mitochondrial alterations in Alzheimer disease, recent works have suggested the therapeutic potential of mitochondrial-targeted antioxidant. On the other hand, autophagy has been demonstrated to play a fundamental role in Alzheimer-related protein stress, and increasing data shows that this pathway is altered in the disease. Moreover, mitochondrial alterations have been related to an insufficient clearance of dysfunctional mitochondria by autophagy. Consequently, different approaches for the removal of damaged mitochondria or to decrease the related oxidative stress in Alzheimer disease have been described. To understand the role of mitochondrial function in Alzheimer disease it is necessary to generate human cellular models which involve living neurons. We have summarized the novel protocols for the generation of neurons by reprogramming or direct transdifferentiation, which offer useful tools to achieve this result.

Figure 1

AD-related alterations of mitochondrial respiratory chain and tricarboxylic acid cycle. Scheme of alterations in protein levels found in Alzheimer disease brains as well as the targets of amyloid-β (Aβ) and phosphorylated Tau (pTau). Oxidative phosphorylation complexes are labeled as CI to CIV. PDH: pyruvate dehydrogenase, α-KG: α-ketoglutarate, α-KGDH: α-ketoglutarate dehydrogenase, OAA: oxaloacetate.

Figure 2

Mitochondrial alterations found in AD. Scheme of the effect of amyloid-β (Aβ) and phosphorylated-Tau (pTau) over mitochondrial dynamics, transport, protein import, membrane permeabilization, and apoptosis as well as actin dynamics. Alterations of the levels of involved proteins found in AD brains are also summarized. DLP1: dynamin-like protein 1, MFF: mitochondrial fission factor, FIS: fission 1, MIEF: mitochondrial elongation factor, MFN1: mitofusin 1, MFN2: mitofusin 2, OPA1: optic atrophy 1, PHB1: prohibitin 1, ABAD: Aβ-binding alcohol dehydrogenase, Prep: presequence protease, VDAC: voltage-dependent anion channel, ANT: adenine nucleotide translocase, CypD: cyclophilin D, Cyt C: cytochrome c, COX: cytochrome c oxidase, Ψ_m: mitochondrial membrane potential, and mtDNA: mitochondrial DNA.