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Review
. 2013 Oct;134(10):506-15.
doi: 10.1016/j.mad.2013.08.007. Epub 2013 Sep 3.

Impaired Mitochondrial Energy Production and ABC Transporter function-A Crucial Interconnection in Dementing Proteopathies of the Brain

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Free PMC article
Review

Impaired Mitochondrial Energy Production and ABC Transporter function-A Crucial Interconnection in Dementing Proteopathies of the Brain

Jens Pahnke et al. Mech Ageing Dev. .
Free PMC article

Abstract

Ageing is the main risk factor for the development of dementing neurodegenerative diseases (NDs) and it is accompanied by the accumulation of variations in mitochondrial DNA. The resulting tissue-specific alterations in ATP production and availability cause deteriorations of cerebral clearance mechanisms that are important for the removal of toxic peptides and its aggregates. ABC transporters were shown to be the most important exporter superfamily for toxic peptides, e.g. β-amyloid and α-synuclein. Their activity is highly dependent on the availability of ATP and forms a directed energy-exporter network, linking decreased mitochondrial function with highly impaired ABC transporter activity and disease progression. In this paper, we describe a network based on interactions between ageing, energy metabolism, regeneration, accumulation of toxic peptides and the development of proteopathies of the brain with a focus on Alzheimer's disease (AD). Additionally, we provide new experimental evidence for interactions within this network in regenerative processes in AD.

Keywords: ABC transporters; ABCA1; ABCA7; ABCB1; ABCC1; Ageing; Alzheimer's disease; Aqp4; Dementia; Energy metabolism; Mitochondria; Neurodegeneration; Parkinson's disease.

Figures

Figure 1
Figure 1. Aβ deposition triggers neurogenesis dependent on ABC transporter expression. ABC transporter dysfunction and Aβ proteopathy impair the neuroregeneration
Graphs were established from quantification of immunofluorescence staining. Procedures were the same as in (Schumacher et al., 2012). (A) Aβ deposition does not significantly alter the quantity of Sox2+ (transcription factor, active only in stem and progenitor cells) stem cells in comparison to non-trangenic littermates. However, ABC transporter-deficiency increases the relative number in APPtg mice (black bars, ABCB10/0 +16%, ABCG20/0 +19%, ABCC10/0 +12%). (B) The pool of DCX+ (doublecortin, a microtubule associated protein which is transiently expressed only in neuronal progenitor cells) neuroblasts is increased in APPtg animals (ctrls +52%, black bars), ABCB10/0 (+71%), ABCG20/0 (+172%), and ABCC10/0 (+52%, not significant) mice versus non-transgenic littermates. A significant difference between APPtg and APPtg/ABC0/0 strains is only observable in the ABCB10/0 strain (−28%). ABC transporter-deficiency leads to a loss of DCX+ cells even in non-transgenic (non-tg) mice (ABCB10/0 −36%; ABCG20/0 −24%) (C) In case of newly generated Calretinin+ neurons, the increase in cell numbers reaches statistical significance in all APPtg mice as compared to non-transgenic littermates (ctrls +164%, ABCB10/0 +59%, ABCG20/0 +357%, ABCC10/0 +109%). In the APPtg lines a significant effect is only observable for the ABCB10/0 strain which is decreased by −62%. In non-tg mice only the deficiency of ABCB10/0 leads to a significant decline in Calretinin+ cell number (−38%). (D) The incorporation rate of BrdU (bromodeoxyuridine a halogenated thymidine analogue) during proliferation showed significant effects only in APPtg controls (+68%) and APPtg/ABCG20/0 (+175%) mice compared to non-tg littermates. Summarizing, ABC transporter dysfunction and Aβ proteopathy impair the neuroregeneration. Numbers of cells are presented relatively to the previously published data on non-tg littermates (white bars, (Schumacher et al., 2012)). Diagrams indicate means +SEM; t-Test: APPtg ctrls vs. APPtg/ABC0/0 strains: * ≤ 0.05; ** ≤ 0.01; n≥4 (males) t-Test: APPtg vs. non-transgenic littermates: + ≤ 0.05; ++ ≤ 0.01; +++ ≤ 0.001; n≥4; (males) t-Test: non-transgenic ctrls vs non-transgenic ABC0/0 strains: # ≤ 0.05; ## ≤ 0.01; n≥4 (males)
Figure 2
Figure 2
A hypothetical outline of interactions within a complex ageing network involving ABC transporters and mitochondria: i) continuous accumulation of mutations in the mitochondrial DNA and ii) decreased ATP-binding-cassette (ABC) transporter function in all cell types (neurons, microglia, astrocytes, neurosphere-forming stem and progenitor cells) closely interact. Increasing numbers of mitochondrial DNA mutations result in mitochondrial dysfunction that lead to increased ROS production and decreased ATP production and availability. Due to the loss of ABC transporter function, neuroregenerative processes are disturbed and the replacement of lost neurons is reduced. Increasing amounts of highly aggregated Aβ shift the microglia phenotype from neuroprotective to neurotoxic, further promoting neurodegeneration and cognitive decline.

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