Amyloid β precursor protein as a molecular target for amyloid β--induced neuronal degeneration in Alzheimer's disease

Abstract

A role of amyloid β (Aβ) peptide aggregation and deposition in Alzheimer's disease (AD) pathogenesis is widely accepted. Significantly, abnormalities induced by aggregated Aβ have been linked to synaptic and neuritic degeneration, consistent with the "dying-back" pattern of degeneration that characterizes neurons affected in AD. However, molecular mechanisms underlying the toxic effect of aggregated Aβ remain elusive. In the last 2 decades, a variety of aggregated Aβ species have been identified and their toxic properties demonstrated in diverse experimental systems. Concurrently, specific Aβ assemblies have been shown to interact and misregulate a growing number of molecular effectors with diverse physiological functions. Such pleiotropic effects of aggregated Aβ posit a mayor challenge for the identification of the most cardinal Aβ effectors relevant to AD pathology. In this review, we discuss recent experimental evidence implicating amyloid β precursor protein (APP) as a molecular target for toxic Aβ assemblies. Based on a significant body of pathologic observations and experimental evidence, we propose a novel pathologic feed-forward mechanism linking Aβ aggregation to abnormalities in APP processing and function, which in turn would trigger the progressive loss of neuronal connectivity observed early in AD.

Keywords: APP; Alzheimer's disease; Aβ; Dying-back degeneration; Neuritic dystrophy; Synaptic degeneration.

Fig. 1

Scheme depicting the domain structure of amyloid β precursor protein (APP). The E1 domain consisting of the growth factor like domain (GFLD) and the copper-binding domain (CuBD). The acidic domain (AcD) and the Kunitz-type inhibitory domain (Kunitz protease inhibitor [KPI], not present in neurons) bridge the E1 and E2 domains. The E2 domain consists of 2 coiled-coil substructures connected through a continuous helix. The amino acid sequence of amyloid β (Aβ)/transmembrane/intracellular (intracytoplasmic domain of APP [AICD]) domains is shown in the lower part of the figure. Asterisks denote amino acids substituted in familiar forms of AD and APP variants. Arrows indicate cleavage sites for both secretases and caspases. Binding motifs for heterotrimeric Go/s proteins (Go/s-BM) and scaffolding proteins (SP-BM; e.g., Fe65, Mint/X11-family proteins, Dab1, c-Jun N-terminal kinase) are underlined. The Aβ sequence is also underlined.

Fig. 2

Pathways for metabolic processing of amyloid β precursor protein (APP). The 2 most prominent metabolic routes and APP proteolytic derivatives are illustrated. APP is substrate for either α- or β-secretase. Therefore, the nonamyloidogenic and the amyloidogenic pathways are mutually exclusive. Whereas several metalloproteinases display α-secretase activity (reviewed by Allison et al., 2003), β-site APP-cleaving enzyme 1 (BACE1) is the only known aspartylprotease with β-secretase activity (reviewed by Kandalepas and Vassar, 2012). Membrane-tethered APP stubs, C83 and C99 (also known as α- and β-carboxy-terminal fragment), are substrates for γ-secretase, a protein complex that includes at least 4 different proteins: anterior pharynx defective 1, nicastrin, presenilin 1 or presenilin 2, and preselinin enhancer-2 (reviewed by Wolfe, 2012).

Fig. 3

Scheme representing physiological and maladaptive regulation of amyloid b precursor protein (APP) signaling and processing. In physiological conditions, the formation of cis and trans homo- and heterodimers of APP is modulated by interactions with transmembrane proteins (e.g., integrins, APLP1), extracellular secreted proteins (e.g., sAPP), or matrix components (e.g., heparan sulfate proteoglycans). These events regulate metabolic processing of APP (preferentially through the nonamyloidogenic pathway) and trigger signaling cascades that functionally modulate synaptic and neuritic plasticity. Binding of amyloid β (Aβ) fibrils to APP abrogates the interaction of APP with physiological ligands and promotes aberrant APP multimerization. These events shift the metabolic processing of APP to the amyloidogenic pathway, spreading Aβ deposition, and trigger dysfunctional signaling cascades leading to synaptic and neuritic degeneration.