Removing Tau Enhances Brain Function in Young Mice

Aggregation of altered tau protein is arguably the primary cause of brain cell death in the late stages of Alzheimer's disease. It is quite fundamental in cells, involved in maintaining the cytoskeletal structure of microtubules, but nonetheless can be removed without any great disruption of function - though the evidence is mixed on whether that means no unwanted side-effects. This approach has been tried in mice altered to generate similar pathology to that of human Alzheimer's disease. Researchers here instead examine the outcome of removing tau in young mice and find that it actually improves the metabolism of the brain and measures of cognitive function. Mice are not humans, but perhaps it is the case that we might all be enhanced by some form of therapy that can greatly reduce levels of tau in the brain, and not just through a greater ability to resist the onset of age-related neurodegeneration.

Tau is a protein that associates with microtubules and is found prominently in the axons of neurons. Abnormal modifications of tau are involved in a number of neurodegenerative diseases, known as tauopathies, which are characterized by the formation of pathological deposits of tau. Hyperphosphorylated or cleaved forms of tau are the principal components of neurofibrillary tangles, one of the neuropathological hallmarks of Alzheimer's disease (AD). Pathological forms of tau generate serious alterations in neuronal activity, affecting synaptic transmission and learning and memory processes, which finally leads to neurodegeneration.

Genetic deletion of tau could be protective. Studies in a mouse model of AD have shown that ablation of tau expression prevents neurotoxicity induced by the amyloid-β peptide and improves cognitive damage. Similarly, tau deletion protects against the effects of stress on neuronal structure and working memory. However, other reports suggest that the absence of tau could have a negative effect on normal brain function.

Pathological forms of tau can impair mitochondrial function, including mitochondrial morphology, transport, and bioenergetics. Interestingly, we found that the expression of pathological tau species, in particular truncated tau, induces mitochondrial fragmentation and bioenergetics failure in neurons. Similarly, phosphorylated tau induces mitochondrial fragmentation and affects the bioenergetics function of mature neurons. Thus, the absence of tau protein in neural cells could prevent the effects on mitochondrial structure and function produced by post-translationally-modified tau.

Considering that limited research has used tau-deficient mouse models and the role of tau on the regulation of mitochondrial function and the resulting implications on cellular and cognitive processes are not entirely clear, a study examining the impact of tau ablation will contribute to the understanding of the physiological function of tau protein in vivo. The present study was conducted in litters of young mice (3 months old) to investigate the effects of tau reduction in hippocampal tissue, to identify the implications of tau on mitochondrial function and behavior during youth.

Our results showed that tau deletion had positive effects on hippocampal cells by decreasing oxidative damage, favoring a mitochondrial pro-fusion state, and inhibiting mitochondrial permeability transition pore (mPTP) formation by reducing cyclophilin D (Cyp-D) protein. More importantly, tau deletion increased ATP production and improved the recognition memory and attentive capacity of juvenile mice. Therefore, the absence of tau enhanced brain function by improving mitochondrial health, which supplied more energy to the synapses. Thus, our work opens the possibility that preventing negative tau modifications could enhance brain function through the improvement of mitochondrial health.

Link: https://doi.org/10.1016/j.redox.2018.07.010

Comments

Excess of tau proteins most likely is harmful for humans. Mice, however, seem to be a very bad model for Alzheimer's.

So I am not holding my breath for this study. It gives useful hints but without
High certainty

Posted by: Cuberat at August 8th, 2018 7:52 AM

Possibly related to the above excerpt --
"...but nonetheless can be removed without any great disruption of function - though the evidence is mixed on whether that means no unwanted side-effects." -- is the following paper:

"Lithium suppression of tau induces brain iron accumulation and neurodegeneration"
eprints.whiterose.ac.uk/104131/1/Lei et al Mol Psych Main Text.pdf

Presumably, there is a therapeutic window.

Posted by: Lou Pagnucco at August 8th, 2018 2:31 PM

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