Oligomeric and fibrillar species of β-amyloid (Aβ42) both impair mitochondrial function in P301L tau transgenic mice

Abstract

We recently provided evidence for a mitochondrial dysfunction in P301L tau transgenic mice, a strain modeling the tau pathology of Alzheimer's disease (AD) and frontotemporal dementia (FTD). In addition to tau aggregates, the AD brain is further characterized by Aβ peptide-containing plaques. When we addressed the role of Aβ, this indicated a synergistic action of tau and Aβ pathology on the mitochondria. In the present study, we compared the toxicity of different Aβ42 conformations in light of recent studies suggesting that oligomeric rather than fibrillar Aβ might be the actual toxic species. Interestingly, both oligomeric and fibrillar, but not disaggregated (mainly monomeric) Aβ42 caused a decreased mitochondrial membrane potential in cortical brain cells obtained from FTD P301L tau transgenic mice. This was not observed with cerebellar preparations indicating selective vulnerability of cortical neurons. Furthermore, we found reductions in state 3 respiration, the respiratory control ratio, and uncoupled respiration when incubating P301L tau mitochondria either with oligomeric or fibrillar preparations of Aβ42. Finally, we found that aging specifically increased the sensitivity of mitochondria to oligomeric Aβ42 damage indicating that oligomeric and fibrillar Aβ42 are both toxic, but exert different degrees of toxicity.

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

“…Moreover, the antiparallel b-sheet organization of Ab(1-40) oligomers has been previously suggested in Habicht et al [19] and is in agreement with previous structural studies carried out on Ab(1-42) oligomers [20,21] as well as on other proteins forming oligomers like b 2 -microglobulin [53] and PrP (prion related protein) peptide [PrP-(82-146)] [54]. Additionally, Ab oligomers are recognized by the A11 antibody.…”

“…Our observations suggest that self-assembling of Ab(1-40) from oligomers to fibrils involves the central (aa [17][18][19][20][21][22][23][24] and C-terminal parts (aa 30-40) of the peptide (Fig. 3).…”

“…Nevertheless, infrared spectroscopy on Ab(1-40) [19] and [20,21] oligomers shows an antiparallel b-sheet organization.…”

Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice

“…Recently, we had shown in vivo that P301L mutant tau was capable of inducing mitochondrial dysfunction and increasing levels of ROS in pR5 mice (4). We had also found an increased mitochondrial vulnerability of pR5 cortical brain cells toward A␤ in vitro (4,14). However, the relative contribution of tau and A␤ remained unclear, as did possible synergistic effects.…”

“…The membrane potential of the inner mitochondrial membrane was measured using the dye tetramethylrhodamine ethyl ester (TMRE) and the dye rhodamine 123 (R123) (4). ATP content was determined using a bioluminescence assay (ViaLighTM HT; Cambrex Bio Science) (14). The total amount of mitochondria was measured using the cell-permeable mitochondria-selective dye.…”