Preventing Alzheimer's disease by means of natural selection

Abstract

The amyloid cascade model for the origin of sporadic forms of Alzheimer's disease (AD) posits that the imbalance in the production and clearance of beta-amyloid is a necessary condition for the disease. A competing theory called the entropic selection hypothesis asserts that the primary cause of sporadic AD is age-induced mitochondrial dysregulation and the following cascade of events: (i) metabolic reprogramming-the upregulation of oxidative phosphorylation in compensation for insufficient energy production in neurons, (ii) natural selection-competition between intact and reprogrammed neurons for energy substrates and (iii) propagation-the spread of the disease due to the selective advantage of neurons with upregulated metabolism. Experimental studies to evaluate the predictions of the amyloid cascade model are being continually retuned to accommodate conflicts of the predictions with empirical data. Clinical trials of treatments for AD based on anti-amyloid therapy have been unsuccessful. We contend that these anomalies and failures stem from a fundamental deficit of the amyloid hypothesis: the model derives from a nuclear-genomic perspective of sporadic AD and discounts the bioenergetic processes that characterize the progression of most age-related disorders. In this article, we review the anomalies of the amyloid model and the theoretical and empirical support for the entropic selection theory. We also discuss the new therapeutic strategies based on natural selection which the model proposes.

At the Crossroads Between Neurodegeneration and Cancer: A Review of Overlapping Biology and Its Implications

“…This corroborates findings from other studies showing that hyperphosphorylated tau is associated with a decrease in OGlcNAcylation [86]. Altered brain glucose metabolism and hyperglycemia have been suggested to contribute to the pathogenesis of AD, and AD has notably been touted as “type 3 diabetes” due to the striking reduction in the utilization of glucose, as well as extensive abnormalities in genes encoding insulin and its related growth factors [87, 88]. AD patients show reduced glucose energy metabolism in affected regions of the brain [89], and the AD brain also shows a marked reduction in GLUT3, the neuronal glucose transporter [90].…”

A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease

“…In the last few decades, many reports have demonstrated the impairment of mitochondrial function in AD. Moreover, a number of lines of biochemical and cell biological evidence have been marshaled in support of a “mitochondrial cascade hypothesis” for the pathogenesis of AD, which proposes that mitochondrial alterations initiate the cascade of pathologies characteristic of the disease 18 – 25 . However, while this possibility is intriguing, it is currently unclear whether the impairment of mitochondrial function in AD 26 – 33 is the cause, the consequence, or merely a “bystander effect” of the biochemical and morphological changes seen in AD 34 , 35 .…”

Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives

“…Both animal models and human studies showed that aging is characterized by a decreased aerobic glycolysis in astrocytes ( Goyal et al, 2017 ) and mitochondrial oxidative phosphorylation in neurons ( Boumezbeur et al, 2010 ; Jiang and Cadenas, 2014 ). It has been proposed that pathological neurons first exhibit mitochondrial dysfunction and compensatory increase in oxidative phosphorylation that results in a competition for a limited energetic resource, i.e., astrocyte-derived lactate, as the fuel of oxidative phosphorylation ( Demetrius and Driver, 2015 ). This competition for energetic resource leads to deleterious consequences on initially healthy neurons in the vicinity of neurons with mitochondrial dysfunction, thereby spreading neurodegeneration and development of the pathological state, from normal aging to neurodegeneration ( Demetrius et al, 2014 ).…”