Unraveling in vivo Functions of Amyloid Precursor Protein: Insights from Knockout and Knockdown Studies

Abstract

The amyloid precursor protein (APP) is a widely expressed transmembrane protein that is cleaved to generate Aβ peptides in the central nervous system and is a key player in the pathogenesis of Alzheimer’s disease. The precise biological functions of APP still remain unclear although various roles have been proposed. While a commonly accepted model argues that Aβ peptides are the cause of onset and early pathogenesis of Alzheimer’s disease, recent discussions challenge this ‘Aβ hypothesis’ and suggest a direct role for APP in this neurodegenerative disease. Loss-of-function studies are an efficient way to elucidate the role of proteins and concurrently a variety of in vitro and in vivo studies has been performed for APP where protein levels have been downregulated and functional consequences monitored. Complete disruption of APP gene expression has been achieved by the generation of APP knockout animal models. Further knockdown studies using antisense and RNA interference have allowed scientists to reduce APP expression levels and have opened new avenues to explore the physiological roles of APP. In the present review, we focus on knockout and knockdown approaches that have provided insights into the physiological functions of APP and discuss their advantages and drawbacks.

Nasal inoculation of an adenovirus vector encoding 11 tandem repeats of Aβ1‐6 upregulates IL‐10 expression and reduces amyloid load in a Mo/Hu APPswe PS1dE9 mouse model of Alzheimer's disease

“…Aβ found in the AD brain is heterogeneous at its carboxyl-terminus, resulting in peptides of 39-43 amino acids. Although the precise biological roles of APP are elusive, studies of over-and under-expression of APP suggest a number of important physiological functions [1,2]. Such functions include neurite outgrowth, synaptogenesis, neurogenesis [3], cell adhesion and migration, axonal transport [4], brain copper homeostasis [5], and brain and somatic development through Notch and Fe65 signaling pathway [6,7].…”

Autophagy, amyloidogenesis and Alzheimer disease

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APP biology in briefAPP is a member of a family of conserved type 1 membrane proteins, which includes in mammals APP-like protein (APLP) 1 and APLP2 (Coulson et al, 2000;Senechal et al, 2006). Although its function remains uncertain, putative physiological roles in trafficking, neurotrophic signaling, cell adhesion and cell signaling have been proposed (Reinhard et al, 2005;Zheng and Koo, 2006;Hoareau et al, 2006).

After APP is synthesized, the mature glycosylated form of APP in the trans-Golgi network (TGN) is delivered to the plasma membrane, where it is fairly rapidly turned over by either of two mechanisms (Fig.

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Amyloid beta mediates memory formation

“…Whether these concentrations of Ab peptides play physiological functions in normal conditions still remains to be determined. Previous studies have implicated APP or its metabolites in synapse formation, maintenance and growth, in neurite extension, and, intriguingly, in synaptic plasticity and learning and memory (Senechal et al 2006). APP knockout mice are impaired in longterm potentiation as well as spatial and avoidance learning and memory (Muller et al 1994;Dawson et al 1999;Seabrook et al 1999).…”