Knockdown of Amyloid Precursor Protein: Biological Consequences and Clinical Opportunities

Abstract

Amyloid precursor protein (APP) and its cleavage fragment Amyloid-β (Aβ) have fundamental roles in Alzheimer's disease (AD). Genetic alterations that either increase the overall dosage of APP or alter its processing to favour the generation of longer, more aggregation prone Aβ species, are directly causative of the disease. People living with one copy of APP are asymptomatic and reducing APP has been shown to lower the relative production of aggregation-prone Aβ species in vitro. For these reasons, reducing APP expression is an attractive approach for AD treatment and prevention. In this review, we will describe the structure and the known functions of APP and go on to discuss the biological consequences of APP knockdown and knockout in model systems. We highlight progress in therapeutic strategies to reverse AD pathology via reducing APP expression. We conclude that new technologies that reduce the dosage of APP expression may allow disease modification and slow clinical progression, delaying or even preventing onset.

Keywords: Alzheimer’s disease; CRISPR; amyloid precursor protein (APP); amyloid-beta; antisense oligonucelotides.

FIGURE 1

Domains of amyloid precursor protein (APP) and the APP-like proteins (APLP) protein family members. APP and its mammalian homologues APLP1 and APLP2 share similar domain architecture including the E1 and E2-domains, which potentially drive dimerisation. APP770, APP751, and APLP2 are characterised by the Kunitz type protease inhibitor domain (KPI) upstream of E2. APP770 includes also the OX2 domain. Both APP and APLPs contain a transmembrane domain (TMD) but only APPs have the Aβ sequence (purple). Created with BioRender.com.

FIGURE 2

Amyloid precursor protein (APP) cleavage. APP can undergo canonical (top) and non-canonical (bottom) processing. In the amyloidogenic pathway (top, right side), APP is processed by β-secretase and γ-secretase resulting in the formation of Aβ peptides, APP intracellular domain (AICD) and sAPPβ. In the non-amyloidogenic pathway (top, left side), APP is cleaved by α-secretase and γ-secretase resulting p3 peptide, AICD, and sAPPα. Meprin-β cleavage (bottom left) generates three soluble APP fragments; the remaining CTF fragment can be further cleaved by γ-secretase giving rise to a smaller fragment indicated by * and AICD. APP cleavage by η-secretase (bottom, middle panel) generates an APP (sAPPη) and a CTFη fragment which can be further processed by either α or β-secretase and then by γ-secretase resulting in the formation of Aη-α/β and a CTFα or β fragment. APP cleavage by δ-secretase (bottom right) gives rise to a fragment which can activate the death cell receptor (DR6) promoting cell death or can be further cleaved to generate a fragment unable to bind the receptor; the remaining CTFδ fragment can be processed by γ-secretase form the intracellular domain AICD. Created with BioRender.com.

FIGURE 3

Proposed roles of amyloid precursor protein (APP) and phenotypes associated to changes in APP level. (A) APP plays a role in many biological processes including maintenance of synapse, transcriptional regulation, plasticity, and neuroprotection. APP is cleaved into biologically active fragments; APP intracellular domain (AICD) translocates to the nucleus where it regulates transcription; APP localises to the neuronal growth cone where it regulates axon growth; APP dimerization occurs at the synapse (in trans and in cis) between two molecules of APP regulating synaptic stability (similar dimerization occurs at the neuromuscular junction). (B) Phenotypes associated with overexpression of wild type APP, APP knockout and ASO-mediated APP modulation. Created with BioRender.com.