Amyloid precursor proteins are protective in Drosophila models of progressive neurodegeneration

Abstract

The processing of Amyloid Precursor Proteins (APPs) results in several fragments, including soluble N-terminal ectodomains (sAPPs) and C-terminal intracellular domains (AICD). sAPPs have been ascribed neurotrophic or neuroprotective functions in cell culture, although β-cleaved sAPPs can have deleterious effects and trigger neuronal cell death. Here we describe a neuroproprotective function of APP and fly APPL (Amyloid Precursor Protein-like) in vivo in several Drosophila mutants with progressive neurodegeneration. We show that expression of the N-terminal ectodomain is sufficient to suppress the progressive degeneration in these mutants and that the secretion of the ectodomain is required for this function. In addition, a protective effect is achieved by expressing kuzbanian (which has α-secretase activity) whereas expression of fly and human BACE aggravates the phenotypes, suggesting that the protective function is specifically mediated by the α-cleaved ectodomain. Furthermore, genetic and molecular studies suggest that the N-terminal fragments interact with full-length APPL activating a downstream signaling pathway via the AICD. Because we show protective effects in mutants that affect different genes (AMP-activated protein kinase, MAP1b, rasGAP), we propose that the protective effect is not due to a genetic interaction between APPL and these genes but a more general aspect of APP proteins. The result that APP proteins and specifically their soluble α-cleaved ectodomains can protect against progressive neurodegeneration in vivo provides support for the hypothesis that a disruption of the physiological function of APP could play a role in the pathogenesis of Alzheimer’s Disease.

Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS

“…Amyloid precursor protein (APP) is a membrane protein that is metabolized to β-amyloid – the main component of Alzheimer’s Disease (AD) plaques (Klunk & Abraham, 1988). While the function of APP in the non-AD brain is unknown, it has been suggested to play a neuroprotective role under normal physiological conditions (Wentzell et al, 2012). Nfkbia , up-regulated 2.8-fold, encodes a cellular protein that inhibits the NF-kB transcription factor (Arenzana-Seisdedos et al, 1995), which contributes to a pro-inflammatory cascade when activated.…”

Amyloid Precursor Proteins Are Dynamically Trafficked and Processed during Neuronal Development

“…Also like mammalian APP, APPL plays important roles in the developing nervous system, participating in the control of neuronal migration and synaptic plasticity (Torroja et al, 1999; Ashley et al, 2005; Ramaker et al, 2013; Soldano et al, 2013; Bourdet et al, 2015). Notably, studies in Drosophila have shown that defects caused by the loss of APPL can be rescued by the expression of human APP 695 (Luo et al, 1992; Wentzell et al, 2012), indicating that these proteins are both structurally and functionally homologous. However, unlike mammalian APP (which is expressed by many cell types), APPL is exclusively expressed in neurons, greatly simplifying an analysis of its biological functions in vivo .…”

Rassignal triggersβ-Amyloid Precursor Protein(APP) expression

“…23 In Drosophila, Appl is specifically expressed in developing neurons [24][25][26] and has been associated with axonal function. [27][28][29][30][31][32] Mora et al, (2012) describes two main phenotypes in photoreceptors for the Appl loss of function mutants: (1) R7 photoreceptor axonal targeting was disrupted and (2) UV light discrimination ability, which is the wavelength captured by R7 neurons, was altered. Abnormal light discrimination was strongly enhanced in individuals that were mutant for Appl and also heterozygous for loss of neurotactin function; this latter gene is involved in axon guidance.…”