Identification of the Alzheimer's disease amyloid precursor protein (APP) and its homologue APLP2 as essential modulators of glucose and insulin homeostasis and growth

Abstract

The amyloid precursor protein (APP), the source of the neurotoxic amyloid beta (A beta) peptide involved in Alzheimer's disease (AD), belongs to a conserved family of related proteins. In mammals, the APP family contains amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2). Whilst a number of activities have been attributed to the APP family, an overall function has not been definitively established. While ablating either the APP or APLP2 gene in mice produces minimal phenotypic change, the combined knockout of these genes in mice causes postnatal mortality. Postnatal survival therefore requires a shared but unknown function of APP and APLP2. To investigate the biochemical basis for the postnatal lethality, plasma was analysed from double knockout mice (APP-/- APLP2-/-) 2 days before birth, at gestational day E17, and from mice at 12-16 h after birth. The postnatal double knockouts had 66% lower plasma glucose levels than their wild-type controls and 50% lower than their single knockout counterparts. Interestingly, the postnatal double knockouts displayed hyperinsulinaemia, as shown by inappropriate plasma insulin levels, given their degree of hypoglycaemia. The single knockout mice also showed hyperinsulinaemia and had 31% lower plasma glucose than the wild-types. While the double knockouts did not survive more than 24 h after birth, the single knockouts reached adulthood and their hypoglycaemia continued. Therefore, APP and APLP2 expression modulates plasma insulin and glucose concentrations. Plasma calcium, magnesium and phosphate were also significantly reduced in the double knockouts compared to the wild-types, and they showed distinctive growth restriction, suggesting the involvement of a metabolic impairment. These results link the expression of the APP and APLP2 genes with glucose homeostasis and growth and therefore identify a novel function for the APP family.

Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors

“…Of particular interest is a recent study by Needham et al that revealed a possible new function of the APP family, namely as modulators of insulin and glucose homeostasis [118]. The study correlated the postnatal lethality in the APP -/-/APLP2 -/-knock-out mice to hyperinsulinemia and low glucose levels.…”

Insulin-like Growth Factor-1 (IGF-1)-induced Processing of Amyloid-β Precursor Protein (APP) and APP-like Protein 2 Is Mediated by Different Metalloproteinases

“…Cells were harvested and analyzed by Western blot assay as described previously (21). Primary antibody concentrations were as follows: 1:2,000 for 6E10 (directed against A␤ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] ) and 1:4,000 for CT11 (directed against the C-terminal 11 amino acids of APLP1), 1:3,000 for 42464 (directed against amino acids 499 -557 of APLP1; cf. 22) and 1:5,000 for DTII (directed against full-length APLP2), 1:1,000 for CT-TACE (directed against the C-terminal 18 amino acids of TACE), and subsequently 1:5,000 for horseradish peroxidase-coupled anti-mouse IgG, anti-rabbit IgG, and protein A.…”

“…Importantly, double knock-out studies in mice demonstrated a crucial role for APLP2 in survival because APP Ϫ/Ϫ /APLP2 Ϫ/Ϫ and APLP1 Ϫ/Ϫ /APLP2 Ϫ/Ϫ mice died within the first week after birth, whereas APP Ϫ/Ϫ /APLP1 Ϫ/Ϫ mice survived (4). Recently, the mechanism for the postnatal lethality in the APP Ϫ/Ϫ / APLP2 Ϫ/Ϫ knock-out mice was correlated to hyperinsulinemia and hypoglycemia, suggesting that APP family proteins are essential modulators of glucose and insulin pathways (5). This is interesting because a relationship between diabetes mellitus and AD has been suggested, and disturbed insulin levels and signaling in AD brains have been observed (6).…”

APP physiological and pathophysiological functions: insights from animal models

“…APP KO mice are viable and fertile but suffer from various defects and abnormalities, such as reduced body and brain weight, decreased size of forebrain commissures, increased frequency and severity of corpus callosum agenesis [28,30], reactive gliosis [28], increased sensitivity to kainate-induced seizures [36], increased copper and iron levels in the cerebral cortex and liver [37,38], upregulated cholesterol and sphingomyelin levels in the brain [39] and decreased plasma glucose levels as well as hyperinsulinemia [40]. Behavioral studies revealed that APP KO mice have decreased locomotor activity, reduced forelimb grip strength and deficits in the Morris water maze task as well as passive avoidance learning [41][42][43].…”