Potent amyloidogenicity and pathogenicity of Aβ43.

The amyloid-β peptide Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer\u27s disease. However, the role of Aβ43, which is found just as frequently in the brains of affected individuals, remains unresolved. We generated knock-in mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygosity was embryonic lethal, indicating that the mutation involves a loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevated Aβ43, impairment of short-term memory and acceleration of amyloid-β pathology, which accompanied pronounced accumulation of Aβ43 in plaque cores similar in biochemical composition to those observed in the brains of affected individuals. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aβ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with the age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic and abundant in vivo

The evolution of Aβ peptide burden in the APP23 transgenic mice: implications for Aβ deposition in Alzheimer disease

Background: High levels of Aβ in the cerebral cortex distinguish demented Alzheimer’s disease (AD) from nondemented elderly individuals, suggesting that decreased amyloid-beta (Aβ) peptide clearance from the brain is a key precipitating factor in AD.Materials and Methods: The levels of Aβ in brain and plasma as well as apolipoprotein E (ApoE) in brain were investigated by enzyme-linked immunosorbent assay (ELISA) and Western blotting at various times during the life span of the APP23 transgenic (Tg) and control mice. Histochemistry and immunocytochemistry were used to assess the morphologic characteristics of the brain parenchymal and cerebrovascular amyloid deposits and the intracellular amyloid precursor protein (APP) deposits in the APP23 Tg mice.Results: No significant differences were found in the plasma levels of Aβ between the APP23 Tg and control mice from 2–20 months of age. In contrast, soluble Aβ levels in the brain were continually elevated, increasing 4-fold at 2 months and 33-fold in the APP23 Tg mice at 20 months of age when compared to the control mice. Soluble Aβ42 was about 60% higher than Aβ40. In the APP23 Tg mice, insoluble Aβ40 remained at basal levels in the brain until 9 months and then rose to 680 µg/g cortex by 20 months. Insoluble A?40 was negligible in non-Tg mice at all ages. Insoluble Aβ42 in APP23 Tg mice rose to 60 µg/g cortex at 20 months, representing 24 times the control Aβ42 levels. Elevated levels of ApoE in the brain were observed in the APP23 Tg mice at 2 months of age, becoming substantially higher by 20 months. ApoE colocalized with Aβ in the plaques. Beta-amyloid precursor protein (βAPP) deposits were detected within the neuronal cytoplasm from 4 months of age onward. Amyloid angiopathy in the APP23 Tg mice increased markedly with age, being by far more severe than in the Tg2576 mice.Conclusions: We suggest that the APP23 Tg mouse may develop an earlier blockage in Aβ clearance than the Tg2576 mice, resulting in a more severe accumulation of Aβ in the perivascular drainage pathways and in the brain. Both Tg mice reflect decreased Aβ elimination and as models for the amyloid cascade they are useful to study AD pathophysiology and therapy

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice

The Cu-binding beta-amyloid precursor protein (APP), and the amyloid Abeta peptide have been proposed to play a role in physiological metal regulation. There is accumulating evidence of an unbalanced Cu homeostasis with a causative or diagnostic link to Alzheimer's disease. Whereas elevated Cu levels are observed in APP knockout mice, APP overexpression results in reduced Cu in transgenic mouse brain. Moreover, Cu induces a decrease in Abeta levels in APP-transfected cells in vitro. To investigate the influence of bioavailable Cu, transgenic APP23 mice received an oral treatment with Cu-supplemented sucrose-sweetened drinking water (1). Chronic APP overexpression per se reduced superoxide dismutase 1 activity in transgenic mouse brain, which could be restored to normal levels after Cu treatment (2). A significant increase of brain Cu indicated its bioavailability on Cu treatment in APP23 mice, whereas Cu levels remained unaffected in littermate controls (3). Cu treatment lowered endogenous CNS Abeta before a detectable reduction of amyloid plaques. Thus, APP23 mice reveal APP-induced alterations linked to Cu homeostasis, which can be reversed by addition of dietary Cu