Glucose metabolism and insulin receptor signal transduction in Alzheimer disease

Abstract

Nosologically, Alzheimer disease is not a single disorder in spite of a common clinical phenotype. Etiologically, two different types or even more exist. (1) In a minority of about 5% or less of all cases, Alzheimer disease is due to mutations of three genes, resulting in the permanent generation of βA4. (2) The great majority (95% or more) of cases of Alzheimer disease are sporadic in origin, with old age as main risk factor, supporting the view that susceptibility genes and aging contribute to age-related sporadic Alzheimer disease. However, disturbances in the neuronal insulin signal transduction pathway may be of central pathophysiological significance. In early-onset familial Alzheimer disease, the inhibition of neuronal insulin receptor function may be due to competitive binding of amyloid beta (Aβ) to the insulin receptor. In late-onset sporadic Alzheimer disease, the neuronal insulin receptor may be desensitized by inhibition of receptor function at different sites by noradrenaline and/or cortisol, the levels of which both increase with increasing age. The consequences of the inhibition of neuronal insulin signal transduction may be largely identical to those of disturbances of oxidative energy metabolism and related metabolism, and of hyperphosphorylation of tau-protein. As far as the metabolism of amyloid precursor protein (APP) in late-onset sporadic Alzheimer disease is concerned, neuronal insulin receptor dysfunction may result in the intracellular accumulation of Aβ and in subsequent cellular damage. In this context, the desensitization of the neuronal insulin receptor in late-onset sporadic Alzheimer disease is different from that occurring in normal aging and early-onset familial Alzheimer disease. In late-onset sporadic Alzheimer disease changes in the brain are similar to those caused by non-insulin-dependent diabetes mellitus.

Introduction

Nosologically, Alzheimer disease is not a single disorder. Evidence has been provided that a small proportion of 5% or less (326 families world-wide) of all Alzheimer cases are caused by missense mutations in presenilin genes 1 or 2 on chromosomes 14 and 1, or in the amyloid precursor protein (APP) gene on chromosome 21, leading to autosomal dominant familial Alzheimer disease with an early onset (Pericak-Vance and Haines, 1995, Tilley et al., 1998; for review, see Rocchi et al., 2003). This difference in inheritance forms the basis of the amyloid cascade hypothesis of Alzheimer disease, which explains the genetically induced increased formation of the APP derivative βA4, which aggregates to form amyloid and plaques (Hardy and Selkoe, 2002). In contrast, the great majority of all Alzheimer cases (95% or more) are sporadic in origin and of late onset. βA4 has not been proven to be necessary for the generation and the development of sporadic Alzheimer disease (Joseph et al., 2001). Thus, the amyloid cascade hypothesis may not apply to sporadic Alzheimer disease.

Susceptibility genes may contribute to the generation of sporadic Alzheimer disease. Best known are allelic abnormalities of the apolipoprotein E (APOE) gene on chromosome 19 which are responsible for both anticipated onset and increase in severity of both inherited and sporadic Alzheimer disease. The are other potential candidate susceptibility genes for sporadic Alzheimer disease (Rocchi et al., 2003). Another aspect not yet considered is the change in the gene expression profile in the brain with aging and particularly the expression of genes for some ATP-ases and proteins with a protective function and active in synaptic transmission Whittemore et al., 1986, Parhad et al., 1995, Salehi et al., 1996, Wu and Lee, 1997, Hung et al., 2000, Jiang et al., 2001, Cho et al., 2002. The age-related changes in the profile of susceptibility genes may participate in the origin of disorders that become manifest late in life and which have a chronic and progressive course. Such a genetic predisposition together with age-related risk factors may then cause the disease (Holness et al., 2000). Age has been found to be a major risk factor for sporadic Alzheimer disease because of multiple changes at the cellular and molecular level (for review, see Hoyer, 1995, Hoyer, 2000c.

Oxidative energy metabolism is important for the undisturbed function and structure of the brain. Both the neurotransmitter acetylcholine and the membrane sterol constituent cholesterol are derived from the glucose metabolite, acetyl-CoA Gibson et al., 1975, Michikawa and Yanagisawa, 1999. ATP is formed from glucose only, and is essential to most cellular and molecular activities such as protein synthesis, sorting, transport and degradation of proteins, and maintenance of synaptic transmission (for review, see Hoyer, 2000a). ATP is of particular functional significance in the maintenance of intra/extracellular ion homeostasis (Erecinska and Silver, 1989), and the correct folding of proteins, and in keeping the endoplasmic reticulum and Golgi apparatus at a pH of 6 Seksek et al., 1995, Verde et al., 1995. ATP-dependent processes such as binding of chaperones to the unfolded state of proteins, its promotion to correct folding and assembly of secretory proteins take place in the lumen of the endoplasmic reticulum (Dorner et al., 1990). It thus becomes obvious that the neuronal glucose/energy metabolism is of central significance to normal cellular and molecular reactions.

There is increasing evidence that neuronal glucose energy metabolism is antagonistically controlled by insulin and cortisol. This short review, therefore, focuses on the ways in which disturbances of the neuronal insulin signal transduction cascade contribute to the cellular and molecular abnormalities occurring in the brain in Alzheimer disease.