Down-Regulation of Energy Metabolism in Alzheimer's Disease is a Protective Response of Neurons to the Microenvironment

Abstract

A central issue in the field of Alzheimer's disease (AD) is to separate the cause from the consequence among many observed pathological features, which may be resolved by studying the time evolution of these features at distinctive stages. In this work, comprehensive analyses on transcriptome studies of human postmortem brain tissues from AD patients at distinctive stages revealed stepwise breakdown of the cellular machinery during the progression of AD. At the early stage of AD, the accumulation of amyloid-β oligomers and amyloid plaques leads to the down-regulation of biosynthesis and energy metabolism. At the intermediate stage, the progression of the disease leads to enhanced signal transduction, while the late stage is characterized by elevated apoptosis. The down-regulation of energy metabolism in AD has been considered by many as a consequence of mitochondrion damage due to oxidative stress. However, the non-existence of enhanced response to oxidative stress and the revelation of intriguing down-regulation patterns of the electron-transport chain at different stages suggest otherwise. In contrast to the damage-themed hypothesis, we propose that the down-regulation of energy metabolism in AD is a protective response of the neurons to the reduced level of nutrient and oxygen supply in the microenvironment. The elevated apoptosis at the late stage of AD is triggered by the conflict between the low level of energy metabolism and high level of regulatory and repair burden. This new hypothesis has significant implication for pharmaceutical intervention of Alzheimer's disease.

Potential hippocampal genes and pathways involved in Alzheimer’s disease: a bioinformatic analysis

“…Previous studies have highlighted the relationship between oxidative phosphorylation and AD. According to a study by Sun et al (2012), an energy deficiency in the brain might be the commonest etiological agent for AD. Shoffner (1997) also showed that functional decreases in the activity of enzymes involved in oxidative phosphorylation appeared to occur in AD and may be related to other neurodegenerative processes, which supports the concept that oxidative phosphorylation plays an important role in the pathophysiology of AD.…”

Metabolic study of Alzheimer’s disease using mutant C. elegans

“…The decreased glucose metabolism in AD could be attributed as a main cause [601][602][603] or protective against AD progression [45] as evidence indicates that impaired mitochondrial bioenergetics may proceed by decades the appearance of disease [426,604]. Various epidemiological studies showed diabetes (metabolic disease with chronic hyperglycemia) as a major risk factor in AD [164] suggesting that induced glucose may increase neurodegeneration.…”

“…This is supported by the observation that reduced glucose metabolism and associated enzyme activities were observed in AD patients [41, 433-435, 437, 511]. In contrast, there is a decrease in Aβ-toxicity after caloric restriction or inhibition of glucose catabolism, which indicates that reduction in glucose-associated metabolism protects against neurodegeneration [31,32,45,401,402,438,512]. These contradictory observations mark glucose metabolism as an important target for studies designed to increase our understanding of the progression of AD.…”

“…Although these findings suggest a possible role between disease progression and dehydrogenase complex activities, we cannot conclude a negative role of DLD containing complexes in accelerating progression of AD or other neurodegenerative diseases. It is possible that the decrease in their activities may, in fact, be a protective effect, induced in diseased brains in an attempt to limit disease progression [45]. The recent demonstration that reduction in dld-1 expression results in an extended lifespan in C. elegans suggests a relationship between the effect of energy metabolism on ageing and its effect on ageingassociated diseases, including Alzheimer's disease (AD) [46].…”

“…The first interpretation is mostly supported by studies conducted at a late stage of the disease on post-mortem brains, making it difficult to assign causality [205,[434][435][436][437]. In contrast, recent studies on mixed stage AD samples support that the down-regulation of energy metabolism is a protective factor, leading to the hypothesis that a decrease in nutrient and oxygen supply minimizes neural activity, thereby decreasing the repair burden [45,438]. This is supported by results from a transgenic mouse model of AD in which upregulation of aerobic respiration is clearly harmful [439].…”