The Role of Amyloid Precursor Protein Processing by BACE1, the β-Secretase, in Alzheimer Disease Pathophysiology

Abstract

Amyloid plaques, composed of the amyloid ␤-protein (A␤), are hallmark neuropathological lesions in Alzheimer disease (AD) brain. A␤ fulfills a central role in AD pathogenesis, and reduction of A␤ levels should prove beneficial for AD treatment. A␤ generation is initiated by proteolysis of amyloid precursor protein (APP) by the ␤-secretase enzyme BACE1. Bace1 knockout (Bace1 ؊/؊ ) mice have validated BACE1 as the authentic ␤-secretase in vivo. BACE1 is essential for A␤ generation and represents a suitable drug target for AD therapy, especially because this enzyme is up-regulated in AD. However, although initial data indicated that Bace1 ؊/؊ mice lack an overt phenotype, the BACE1-mediated processing of APP and other substrates may be important for specific biological processes. In this minireview, topics range from the initial identification of BACE1 to the fundamental knowledge gaps that remain in our understanding of this protease. We address pertinent questions such as putative causes of BACE1 elevation in AD and discuss why, nine years since the identification of BACE1, treatments that address the underlying pathological mechanisms of AD are still lacking. Alzheimer Disease AD2 is the most common form of dementia, afflicting over 29 million people worldwide, a figure anticipated to rise exponentially within decades. Although the etiology remains enigmatic, AD appears to be brought about by both genetic and non-genetic factors. ϳ5% of AD cases are familial (FAD), caused by autosomal dominant mutations in either APP or the PS genes. The underlying cause(s) remain elusive for the majority of sporadic AD cases, although specific risk factors have been identified and include aging, the apolipoprotein E4 allele, certain vascular diseases, and TBI (1).Several major pathologies are observed in AD, and the amyloid hypothesis states that A␤ plays a critical early role, triggering a complex pathological cascade that leads to neurodegeneration (2). A strong genetic correlation exists between FAD and a neurotoxic form of fibrillogenic A␤, A␤42 (3). Pre-symptomatic FAD patients exhibit A␤42 elevations or elevations in A␤42 levels relative to levels of the less fibrillogenic peptide, A␤40, indicating that A␤42 may initiate pathophysiology. Patients with additional copies of the APP gene exhibit total A␤ overproduction and develop early-onset AD (1, 4). Data point toward a critical role for A␤42 in AD etiology, and strategies to lower brain A␤42 levels should be therapeutically beneficial in AD. A␤ GenerationA␤ is formed from endoproteolysis of APP, a type 1 membrane protein (Fig. 1) (5). BACE1 (␤-site APP-cleaving enzyme 1) is essential for initiating A␤ generation and cleaves the APP Asp ϩ1 residue to form the A␤ N terminus, APPs␤, and a C-terminal fragment, C99. BACE1 cleavage of APP is a prerequisite for ␥-secretase-mediated cleavage, and C99 is proteolyzed by ␥-secretase (a protein complex containing PS), which generates an AICD and A␤. This imprecise cleavage produces A␤ variants, including those ending at residues 40 ...

Lipid composition influences the release of Alzheimer's amyloid β‐peptide from membranes

“…3 Ab is produced by two sequential proteolytic cleavages of the amyloid precursor protein (APP) by b-and c-secretases within the membrane. 4,5 Thus, Ab-membrane interactions are of critical importance in understanding the behavior of Ab within the plasma membrane and the mechanism through which it exerts its toxic effects.…”

Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of γ-secretase using synthetic antibodies

“…The principal neuropathological hallmark of AD is the presence of senile plaques composed of dystrophic neurites surrounding extracellular aggregates of Aβ peptides (1). Aβ peptides are liberated from amyloid precursor proteins (APP) by the concerted action of β-site APP cleaving enzyme 1 and γ-secretase (2,3). γ-Secretase is a macromolecular complex consisting of presenilin 1 or presenilin 2 (PS1 or PS2), anterior-pharynx-defective 1 (APH-1), nicastrin (NCT), and presenilin enhancer 2 (PEN-2) that catalyzes intramembranous proteolysis of several membrane-tethered substrates (4).…”

Alzheimer Disease Aβ Production in the Absence of S-Palmitoylation-dependent Targeting of BACE1 to Lipid Rafts

“…In addition, BACE1 also cleaves to a lesser extent within the A␤ domain between Tyr 10 and Glu 11 (␤Ј-cleavage site). Processing of APP at these sites results in the shedding/secretion of the large ectodomain (sAPP␤) and generating membrane-tethered C-terminal fragments ϩ1 and ϩ11 (␤-CTF) (5). The multimeric ␥-secretase cleaves at multiple sites within the transmembrane domain of ␤-CTF, generating C-terminal heterogeneous A␤ peptides (ranging in length between 38 and 43 residues) that are secreted, as well as cytosolic APP intracellular domains (6).…”