Membrane Aging as the Real Culprit of Alzheimer's Disease: Modification of a Hypothesis

Abstract

Our previous studies proposed that Alzheimer's disease (AD) is a metabolic disorder and hypothesized that abnormal brain glucose metabolism inducing multiple pathophysiological cascades contributes to AD pathogenesis. Aging is one of the great significant risk factors for AD. Membrane aging is first prone to affect the function and structure of the brain by impairing glucose metabolism. We presume that risk factors of AD, including genetic factors (e.g., the apolipoprotein E ε4 allele and genetic mutations) and non-genetic factors (such as fat, diabetes, and cardiac failure) accelerate biomembrane aging and lead to the onset and development of the disease. In this review, we further modify our previous hypothesis to demonstrate "membrane aging" as an initial pathogenic factor that results in functional and structural alterations of membranes and, consequently, glucose hypometabolism and multiple pathophysiological cascades.

Keywords: Alzheimer’s disease; Amyloid-β; Membrane aging; Thiamine.

Fig.1

The diagram of relationship between membrane aging and AD. Due to the cause of genetic and non-genetic factors, membrane aging results in the alteration of membrane structure and function, leading to the changes of membrane permeability and the impairment of transmembrane transportation. The maintenance of normal biological functions in cells needs abundant energy metabolism and across-membrane transportation of a great quantity of substrates and key molecules for energy metabolism. Thus, the insufficiency of energy metabolism will cause multiple pathophysiological changes such as glucose hypometabolism, thiamine deficiency, inflammatory responses, etc. and finally lead to AD.