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01.12.2014 | Research article | Ausgabe 1/2014 Open Access

Molecular Neurodegeneration 1/2014

Increased mtDNA mutations with aging promotes amyloid accumulation and brain atrophy in the APP/Ld transgenic mouse model of Alzheimer’s disease

Molecular Neurodegeneration > Ausgabe 1/2014
Lokesh Kukreja, Gregory C Kujoth, Tomas A Prolla, Fred Van Leuven, Robert Vassar
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1750-1326-9-16) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

LK bred the mice, performed the experiments, and wrote the manuscript. RV conceived of the study, participated in its design and coordination, and edited the manuscript. GCK and TAP provided PolgAD257A/D257A mitochondrial DNA mutator mice, and FVL provided APPV717I (APP/Ld) mice. All authors participated in the interpretation of results, read and approved the final manuscript.



The role of mitochondrial dysfunction has long been implicated in age-related brain pathology, including Alzheimer’s disease (AD). However, the mechanism by which mitochondrial dysfunction may cause neurodegeneration in AD is unclear. To model mitochondrial dysfunction in vivo, we utilized mice that harbor a knockin mutation that inactivates the proofreading function of mitochondrial DNA polymerase γ (PolgA D257A), so that these mice accumulate mitochondrial DNA mutations with age. PolgA D257A mice develop a myriad of mitochondrial bioenergetic defects and physical phenotypes that mimic premature ageing, with subsequent death around one year of age.


We crossed the D257A mice with a well-established transgenic AD mouse model (APP/Ld) that develops amyloid plaques. We hypothesized that mitochondrial dysfunction would affect Aβ synthesis and/or clearance, thus contributing to amyloidogenesis and triggering neurodegeneration. Initially, we discovered that Aβ42 levels along with Aβ42 plaque density were increased in D257A; APP/Ld bigenic mice compared to APP/Ld monogenic mice. Elevated Aβ production was not responsible for increased amyloid pathology, as levels of BACE1, PS1, C99, and C83 were unchanged in D257A; APP/Ld compared to APP/Ld mice. However, the levels of a major Aβ clearance enzyme, insulin degrading enzyme (IDE), were reduced in mice with the D257A mutation, suggesting this as mechanism for increased amyloid load. In the presence of the APP transgene, D257A mice also exhibited significant brain atrophy with apparent cortical thinning but no frank neuron loss. D257A; APP/Ld mice had increased levels of 17 kDa cleaved caspase-3 and p25, both indicative of neurodegeneration. Moreover, D257A; APP/Ld neurons appeared morphologically disrupted, with swollen and vacuolated nuclei.


Overall, our results implicate synergism between the effects of the PolgA D257A mutation and Aβ in causing neurodegeneration. These findings provide insight into mechanisms of mitochondrial dysfunction that may contribute to the pathogenesis of AD via decreased clearance of Aβ.
Additional file 1: Figure S1: PolgA D257A mutation does not affect endogenous mouse APP protein levels. (A) Brain homogenates were prepared from D257A; APP/Ld, D257A, APP/Ld, and wild type mice and 10 μg total protein per lane was randomly loaded and subjected to immunoblot analysis using anti-APP N-terminal antibody (22C11). Immunoblot signals were normalized to Ponceau S staining intensities in a given lane. The numbers on immunoblot correspond to a mouse with a specific genotype as denoted in the legend key (box). (B) APP immunosignals in (A) were measured and expressed as percentage of mean wild-type APP level. Note that endogenous APP levels were not significantly different between wild-type and D257A mice (mean ± SEM; **p < 0.01; Student’s t-test). (TIFF 1 MB)
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