Cellular Cofactors for Amyloid β-Peptide-Induced Cell Stress: Moving from Cell Culture to in Vivo

Abstract

Molecular mechanisms underlying Alzheimer’s disease (AD) can be divided into inciting pathogenic factors and those more likely to be associated with amplification of cell stress once the disease process is already under way; the latter are termed progression factors. In view of the protracted clinical course of AD, evolving over years, both processes are relevant to the inexorable decline in neuronal function, both mechanistically and therapeutically. Mutations in β-amyloid precursor protein (βAPP) and presenilins 1 and 2, resulting in increased generation of amyloid β-peptide (Aβ) spanning residues 1–42, have been linked to the pathogenesis of familial AD. 1-4 An emerging role for compromised Aβ clearance and degradation, possibly involving the low density lipoprotein receptor-related protein (LRP), apolipoprotein E (apoE), and/or α2-macroglobulin, has been suggested to contribute to sporadic AD. 5-8 Though other mechanisms certainly remain to be discovered, these data contribute to an increasing body of evidence connecting Aβ as a pathogenetic factor central to neuronal dysfunction underlying AD. Although studies of βAPP biology have advanced to sophisticated analyses of presenilin association with intracellular signaling molecules 9 and subcellular compartmentalization of βAPP processing, 10-14 analysis of mechanisms of Aβ-induced cellular stress are at a less advanced stage. Despite our relative lack of knowledge, understanding how Aβ triggers changes in cellular properties is clearly an essential part of any formulation of the amyloid hypothesis. 15 Why, then, has the search for progression factors in the biology of Aβ been so elusive? An analogy with the blood coagulation mechanism is pertinent. For many years, thrombin, the final enzyme in the procoagulant pathway, was known to cleave plasma protein C, forming an important antithrombotic regulator, activated protein C. 16 There was an apparent paradox as, in vitro, the amounts of thrombin required, the concentration of divalent cations, and the rate of activated protein C formation suggested that this reaction, as it occurs in a purified system, was physiologically irrelevant. 16 The solution to this quandary was provided by the identification of a novel endothelial cell cofactor, the integral membrane protein thrombomodulin. In the presence of thrombomodulin, thrombin-mediated activation of protein C occurred rapidly with physiological concentrations of reactants and cations. 16 The contribution of such cellular cofactors to many biological systems is accepted as a given. In this regard, what types of cellular cofactors have been identified based on their interaction with Aβ? Progression factors relevant to AD exacerbate cell stress in an environment created by the pathogenetic factors. There are many candidate progression factors, such as cytokines, 17 complement activation, 18-20 reactive oxygen intermediates (ROIs), 21-24 and other products of activated microglia and/or astrocytes. Such mediators and other mechanisms, including elevated levels of cytosolic calcium, 24 are likely to be placed distally in pathways of cellular dysfunction. Thus, by the time neurons are bathed in proinflammatory cytokines and the environment is characterized by ubiquitous ROIs and elevated intracellular calcium, cellular dysfunction is likely to be quite advanced. However, another class of cell-associated progression factors relevant to AD are those selectively engaged by pathophysiologically relevant forms of Aβ at nanomolar concentrations. These are described below, grouped into several categories.