Autophagy in Tauopathies Such as Alzheimer's Disease

Autophagy is the name given to a collection of maintenance processes responsible for tagging and recycling damaged, excess, or harmful proteins and structures in the cell. Better maintenance of molecular machinery means a better operation of cells and tissues. Upregulation of autophagy is a feature of many of the approaches shown to modestly slow aging in animal studies, those that mimic some of the biochemistry of calorie restriction. Calorie restriction itself is thought to improve health and longevity primarily through autophagy.

Here, researchers look at autophagy in the context of neurodegenerative conditions. Autophagy targeted at mitochondria, mitophagy, is particularly important to cell function given the importance of mitochondrial production of chemical energy store molecules, ATP, in energy-hungry tissues such as the brain. Further, given that toxic protein aggregates feature prominently in neurodegenerative conditions, and autophagy assists in clearing aggregates, this is another reason to study autophagy in this context.

That said, near all of the presently available approaches to upregulate autophagy, such as pharmacological means of increasing NAD levels via derivatives of vitamin B3, are not as good as either exercise or calorie restriction. Animal studies show that mTOR inhibition via rapamycin is in fact better than exercise (but not calorie restriction) when it comes to beneficial outcomes on health and life span, but rapamycin has downsides - it is an immunosuppressant. Efforts to produce drugs that inhibit mTOR without these undesirable side-effects are still underway.

The emerging role of autophagy and mitophagy in tauopathies: From pathogenesis to translational implications in Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, affecting more than 55 million individuals worldwide in 2021. In addition to the "amyloid hypothesis," an increasing number of studies have demonstrated that phosphorylated tau plays an important role in AD pathogenesis. Both soluble tau oligomers and insoluble tau aggregates in the brain can induce structural and functional neuronal damage through multiple pathways, eventually leading to memory deficits and neurodegeneration.

Autophagy is an important cellular response to various stress stimuli and can generally be categorized into non-selective and selective autophagy. Recent studies have indicated that both types of autophagy are involved in AD pathology. Among the several subtypes of selective autophagy, mitophagy, which mediates the selective removal of mitochondria, has attracted increasing attention because dysfunctional mitochondria have been suggested to contribute to tauopathies.

In this review, we summarize the latest findings on the bidirectional association between abnormal tau proteins and defective autophagy, as well as mitophagy, which might constitute a vicious cycle in the induction of neurodegeneration. Neuroinflammation, another important feature in the pathogenesis and progression of AD, has been shown to crosstalk with autophagy and mitophagy. Additionally, we comprehensively discuss the relationship between neuroinflammation, autophagy, and mitophagy. By elucidating the underlying molecular mechanisms governing these pathologies, we highlight novel therapeutic strategies targeting autophagy, mitophagy and neuroinflammation, such as those using rapamycin, urolithin A, spermidine, curcumin, nicotinamide, and actinonin, for the prevention and treatment of AD.