Impairments in Brain Bioenergetics in Aging and Tau Pathology: A Chicken and Egg Situation?

Abstract

The brain is the most energy-consuming organ of the body and impairments in brain energy metabolism will affect neuronal functionality and viability. Brain aging is marked by defects in energetic metabolism. Abnormal tau protein is a hallmark of tauopathies, including Alzheimer’s disease (AD). Pathological tau was shown to induce bioenergetic impairments by affecting mitochondrial function. Although it is now clear that mutations in the tau-coding gene lead to tau pathology, the causes of abnormal tau phosphorylation and aggregation in non-familial tauopathies, such as sporadic AD, remain elusive. Strikingly, both tau pathology and brain hypometabolism correlate with cognitive impairments in AD. The aim of this review is to discuss the link between age-related decrease in brain metabolism and tau pathology. In particular, the following points will be discussed: (i) the common bioenergetic features observed during brain aging and tauopathies; (ii) how age-related bioenergetic defects affect tau pathology; (iii) the influence of lifestyle factors known to modulate brain bioenergetics on tau pathology. The findings compiled here suggest that age-related bioenergetic defects may trigger abnormal tau phosphorylation/aggregation and cognitive impairments after passing a pathological threshold. Understanding the effects of aging on brain metabolism may therefore help to identify disease-modifying strategies against tau-induced neurodegeneration.

Spermidine Rescues Bioenergetic and Mitophagy Deficits Induced by Disease-Associated Tau Protein

“…Recently, the group of Jürgen Götz also demonstrated that P301L tau impacts the mitophagy process in mammalian cell culture models and C. elegans [ 12 ]. In line with this, studies using therapeutic strategies aimed at improving mitochondrial function have reported protective effects in modulating ATP production, improving neuronal survival and attenuating brain atrophy and neuroinflammation in pre-clinical models of tauopathies [ 10 , 11 , 13 , 14 , 15 ].…”

Mitochondria Transfer in Brain Injury and Disease

“…Mitochondrial dysfunction has been observed in a wide range of brain states and pathologies, including normal brain aging, brain injury, and disease [ 1 ]. Often depicted as the powerhouses of the cell, mitochondria are not only the main generators of energy in the form of adenosine triphosphate (ATP) via oxidative phosphorylation (OXPHOS) and glycolysis, but they are also involved in other processes such as calcium homeostasis and apoptosis [ 2 , 3 ]. The term mitochondrial dysfunction encompasses a range of mitochondrial deficits, ranging from bioenergetic impairment, oxidative stress, mitophagy dysfunction, and altered mitochondrial dynamics.…”

“…As one of the most highly energy-demanding organs in the body [ 4 ], the brain is particularly susceptible to mitochondrial impairments, and research has shown that mitochondrial dysfunction plays a crucial role in the pathogenesis of brain disorders [ 1 , 5 , 6 , 7 , 8 ]. As a result, a wide range of therapeutics targeting mitochondrial dysfunction in the brain have been tested, including pharmacologic approaches (neuroactive steroids, antioxidants, phenylpropanoids) [ 9 , 10 , 11 , 12 , 13 , 14 ] and lifestyle interventions (diet, exercise) [ 3 , 15 , 16 ]. However, the multifaceted and sometimes opposing modes of mitochondrial dysfunction in disease pathology render it difficult to target mitochondrial dysfunction as a whole.…”

Age-dependent accumulation of tau aggregation in Caenorhabditis elegans

“…Recent research, however, has highlighted the importance and complexity of the protein tau in these disorders. Age-related changes in tau have been shown to impair bioenergetics (reviewed in (Grimm, 2021)), autophagy (Chatterjee et al, 2021), calcium consumption (Datta et al, 2021), and other cellular events. In addition, structural studies have shown that tau adopts different conformations in disease that might have different disease causation capabilities (Oakley et al, 2020;Scheres et al, 2020;Shi et al, 2021).…”