Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy

Abstract

Insoluble intracellular aggregation of tau proteins into filaments and neurodegeneration are histopathological hallmarks of Alzheimer disease (AD) and other tauopathies. Recently, prefibrillar, soluble, oligomeric tau intermediates have emerged as relevant pathological tau species; however, the molecular mechanisms of neuronal responses to tau oligomers are not fully understood. Here, we show that hippocampal neurons in six-month-old transgenic mouse model of tauopathy, THY-Tau22, are enriched with oligomeric tau, contain elongated mitochondria, and display cellular stress, but no overt cytotoxicity compared to the control mice. The levels of several key mitochondrial proteins were markedly different between the THY-Tau22 and control mice hippocampi including the mitochondrial SIRT3, PINK1, ANT1 and the fission protein DRP1. DNA base excision repair (BER) is the primary defense system against oxidative DNA damage and it was elevated in six-month-old transgenic mice. DNA polymerase β, the key BER DNA polymerase, was enriched in the cytoplasm of hippocampal neurons in six-monthold transgenic mice and localized with and within mitochondria. Polβ also co-localized with mitochondria in human AD brains in neurons containing oligomeric tau. Most of these altered mitochondrial and DNA repair events were specific to the transgenic mice at 6 months of age and were not different from control mice at 12 months of age when tau pathology reaches its maximum and oligomeric forms of tau are no longer detectable. In summary, our data suggests that we have identified key cellular stress responses at early stages of tau pathology to preserve neuronal integrity and to promote survival. To our knowledge, this work provides the first description of multiple stress responses involving mitochondrial homeostasis and BER early during the progression of tau pathology, and represents an important advance in the etiopathogenesis of tauopathies.

Tau Oligomers Neurotoxicity

“…A very interesting hypothesis is proposed by Zheng et al [103], who believe that in the early phase of tau pathology, soluble TauOs may stimulate protective processes promoting mitochondrial energy production and neuronal survival. mtDNA adheres to the IMM, from where ROS are released, so it is constantly exposed to oxidative damage.…”

“…However, there is a DNA repair mechanism in the mitochondria that is classified as DNA base excision repair (BER). In neurons in which tau oligomerization is present, the mitochondrial structure changes, and the activity of DNA repair processes increases [103]. Zheng et al [103] investigated the protective mechanism stimulated by soluble TauOs in the mitochondria of the CA1 neurons of 6-mo THY-Tau22 mice expressing human tau46 mutated at positions G272V and P301S.…”

“…In neurons in which tau oligomerization is present, the mitochondrial structure changes, and the activity of DNA repair processes increases [103]. Zheng et al [103] investigated the protective mechanism stimulated by soluble TauOs in the mitochondria of the CA1 neurons of 6-mo THY-Tau22 mice expressing human tau46 mutated at positions G272V and P301S. Toxic TauOs were detected with TOC1, phospho-Tau (Ser202, Thr205) AT8, and phospho-Tau (Thr212) antibodies.…”

Insights into Disease-Associated Tau Impact on Mitochondria

“…These findings were reproduced in a recent study showing that increased levels of leucine-rich repeat kinase 2 (LRRK2), which is involved in PD, enhanced tau neurotoxicity by stabilizing the actin cytoskeleton, promoting DRP1 mislocalization and mitochondrial elongation [ 137 ]. Interestingly, mitochondrial elongation was already observed at the early stages of tau pathology in THY-Tau22 mice, when hippocampal Ca1 neurons are enriched with tau oligomers [ 138 ]. In these mice, DRP1 levels were significantly decreased at six months of age compared to age-matched wild-type littermates, whereas no differences were observed at 12 months of age.…”

Cerebrospinal fluid oxidative stress markers in Alzheimer's disease

“…Pathological and experimental studies demonstrated that, in AD, impairment of mitochondrial function causes bioenergetic deficiency, intracellular calcium imbalance, 10 and oxidative stress, thereby aggravating the effect of amyloid beta (Aβ) 11 and tau pathologies, 12 leading to synaptic dysfunction, 13 cognitive impairment, and memory loss. Liraglutide, an s glucagon‐like peptide‐1 (GLP‐1) agonist, is a drug to treat diabetes but also has ability to reduce oxidative stress 14 .…”