Bioenergetics breakdown in Alzheimer's disease: targets for new therapies

Abstract

Alzheimer's disease is rapidly growing worldwide and yet there is no cure for it. Currently available drugs only provide symptomatic relief and do not intervene in disease process sufficiently enough to prevent or cure it. Characteristic features of this disease are decline in neuronal mass and cognitive functions. The most dominant hypothesis proposed for pathogenesis of this disease is called "amyloid hypothesis". It states that excessive production of amyloid peptides called abeta peptides (Aβ) is the underlying cause of neuronal death and dysfunction. However, recent drugs designed based on amyloid hypothesis have failed in clinical trails, demanding fresh assessment. Early and persistent molecular events in this disease progression are energy deficiency and high oxidative stress in the neurons. Our review will put together a disease model based on known human and animal data with regards to breakdown in neuronal energy generation. The model will integrate energy deficits as the cause of neuronal dysfunction and abeta peptide production culminating in catastrophic loss of cognitive functions. Finally, based on this model, we will also suggest enzyme targets in neuronal bioenergetics pathway for design and development of new disease modifying therapies.

Keywords: Alzheimer's disease; amyloid hypothesis; neuronal energy; new therapeutics.

Figure 1

Amyloid hypothesis of Alzheimer's Disease. The classic amyloid hypothesis cascade of events is shown here. The main features are overproduction of Aβ peptides by secretase cleavage, peptide aggregation followed by neurotoxicity, tau phosphorylation, plaque and neurofibrillary tangle (NFT) formation with end result of cognitive loss and Alzheimer's disease.

Figure 2

Bioenergetics of neurodegeneration model (BEND model). An “energy deprivation” based model of Alzheimer's is proposed. The model states that known disease risk factors trigger molecular pathways, which leads to decrease in enzyme activities important in cellular energy generation. Energy defects can result in neuronal dysfunction/loss, BACE-1 induction and cognitive decline.