Amyloid beta (Aβ) peptide modulators and other current treatment strategies for Alzheimer's disease (AD)

Abstract

Introduction: Alzheimer's disease (AD) is a common, progressive neurological disorder whose incidence is reaching epidemic proportions. The prevailing "amyloid cascade hypothesis," which maintains that the aberrant proteolysis of beta-amyloid precursor protein (βAPP) into neurotoxic amyloid beta (Aβ) peptides is central to the etiopathology of AD, continues to dominate pharmacological approaches to the clinical management of this insidious disorder. This review is a compilation and update on current pharmacological strategies designed to down-regulate Aβ42 peptide generation in an effort to ameliorate the tragedy of AD. Areas covered: This review utilized online data searches at various open online-access websites including the Alzheimer Association, Alzheimer Research Forum; individual drug company databases; the National Institutes of Health (NIH) Medline; Pharmaprojects database; Scopus; inter-University research communications; and unpublished research data. Expert opinion: Anti-acetylcholinesterase-, chelation-, N-methyl-D-aspartate (NMDA) receptor antagonist-, statin-, Aβ immunization-, β-secretase-, γ-secretase-based, and other strategies to modulate βAPP processing, have dominated pharmacological approaches directed against AD-type neurodegenerative pathology. Cumulative clinical results of these efforts remain extremely disappointing, and have had little overall impact on the clinical management of AD. While a number of novel approaches are in consideration and development, to date there is still no effective treatment or cure for this expanding healthcare concern.

Figure 1

This diagram depicts the essentials of beta-amyloid precursor protein (βAPP) proteolytic cleavage system [64]. The 770 amino acid βAPP holoprotein is an extremely abundant polytopic type 1 neuronal membrane-spanning glycoprotein that can be processed via a neurotrophic (non-amyloidogenic) or amyloidogenic signaling pathway. In the neurotrophic (non-amyloidogenic) pathway, βAPP is first cleaved by a distintegrin and metallo-protease (ADAM) class of enzymes possessing α-secretase activity. This occurs 12 amino acids from the transmembrane domain of βAPP. This cleavage generates a soluble βAPP ectodomain called sAPPα and a C-terminal fragment (C83; which is further processed by γ-secretase, leading to a secreted p3-peptide). The transmembrane portion of βAPP that gives rise to sAPPα via the α-secretase-mediated pathway supports non-amyloidogenic, neuritogenic and neurotrophic signaling. Proteases similar to α-secretase are essential for a wide range of biological processes, such as cell adhesion and embryonic development. In the alternate amyloidogenic pathway βAPP is sequentially cleaved, first by β-secretase (beta-amyloid cleavage enzyme 1, or BACE1) within the ectodomain of βAPP close to the transmembrane domain, and then by γ-secretase, resulting in the generation of the soluble βAPP ectodomain (βAPPsβ), and the formation of the membrane-bound C-terminal fragment C99 (the C-terminal 99 amino acid peptide of βAPP). The γ-secretase next cleaves C99 giving rise to soluble Aβ-peptides (Aβ), chiefly Aβ40 and Aβ42 peptides, and secretion and the formation of the βAPP intracellular domain AICD which may function as a gene expression regulator. Over time soluble Aβ-peptides aggregate to form insoluble, pathogenic senile plaques (SP); trace metals appear to aid in this aggregation (see text) [–103]. ‘Vibrational’ molecular movement of portions of the βAPP transmembrane polypeptide chain within the hydrophobic membrane (movement depicted by a hatched vertical line next to βAPP) may transiently expose the γ-secretase cleavage site to the aqueous cytoplasmic environment (see text). Notably, the membrane depicted in this drawing may be that of the endoplasmic reticulum, Golgi apparatus or neuronal plasma membrane, so amyloidogenic cleavage of βAPP into Aβ40 or Aβ42 peptides may culminate in either intracellular or extracellular Aβ peptide evolution with ensuing neurotoxic events in that compartment [–8]. Aβ peptides are intensely hydrophobic, and these self-aggregating 40 (Aβ40) and 42 (Aβ42) amino acid peptides accumulate preferentially within, respectively, the microvasculature and senile plaque (SP) cores in AD brain [–,–23]. The activity of the γ-secretase complex (containing βAPP, PS1 and nicastrin and associated peptides) is thought to be rate limiting in Aβ40 and Aβ42 peptide generation. As previously reviewed, the membrane-integral protein nicastrin and the βAPP sorting receptor sortilin-1 (SORL1) also direct βAPP trafficking, and down-regulation of SORL1 may lead to over activation of the amyloidogenic β-γ secretase axis and increased generation of Aβ peptides, both in AD brain and in stressed human brain cell models in vitro [–28,64]. SORL-1 is known to interact with apoE which functions in part as a major cholesterol transporter [–29,64,94]. Selective Aβ42-lowering agents or secretase inhibitors deigned to target β-secretase (BACE1) and in particular γ-secretase (PS1)-mediated Aβ peptide production are currently a principal research and development area, and their successful implementation are an important pharmacotherapeutic strategic goal for future AD treatment. Interactions between lipids, cholesterol, and the various βAPP-processing secretases and βAPP-associated proteins are highly complex. It appears that Aβ peptide production is favored in cholesterol-rich lipid raft domains [,,–103]. While βAPP neurobiology is one of the most intensively studied areas of contemporary neurodegenerative disease research, many of the mechanistic details of βAPP proteolysis, including βAPP-membrane and βAPP-secretase interactions, remain incompletely understood.