Menglan Yuan

Presenilins are required for γ -secretase cleavage of β -APP and transmembrane cleavage of Notch-1

Presenilins are required for γ -secretase cleavage of β -APP and transmembrane cleavage of Notch-1

Altered Metabolism of the Amyloid β Precursor Protein Is Associated with Mitochondrial Dysfunction in Down's Syndrome

Most Downs syndrome (DS) patients develop Alzheimers disease (AD) neuropathology. Astrocyte and neuronal cultures derived from fetal DS brain show alterations in the processing of amyloid beta precursor protein (AbetaPP), including increased levels of AbetaPP and C99, reduced levels of secreted AbetaPP (AbetaPPs) and C83, and intracellular accumulation of insoluble Abeta42. This pattern of AbetaPP processing is recapitulated in normal astrocytes by inhibition of mitochondrial metabolism, consistent with impaired mitochondrial function in DS astrocytes. Intracellular Abeta42 and reduced AbetaPPs are also detected in DS and AD brains. The survival of DS neurons is markedly increased by recombinant or astrocyte-produced AbetaPPs, suggesting that AbetaPPs may be a neuronal survival factor. Thus, mitochondrial dysfunction in DS may lead to intracellular deposition of Abeta42, reduced levels of AbetaPPs, and a chronic state of increased neuronal vulnerability.

Amyloid |[beta]| interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease

Amyloid β protein (Aβ) deposition in the brain is a hallmark of Alzheimers disease (AD). The fibrillar form of Aβ is neurotoxic, although the mechanism of its toxicity is unknown. We showed that conversion of Aβ to the fibrillar form markedly increased binding to specific neuronal membrane proteins, including amyloid precursor protein (APP). Nanomolar concentrations of fibrillar Aβ bound cell-surface holo-APP in cortical neurons. Reduced vulnerability of cultured APP-null neurons to Aβ neurotoxicity suggested that Aβ neurotoxicity involves APP. Thus Aβ toxicity may be mediated by the interaction of fibrillar Aβ with neuronal membrane proteins, notably APP. An Aβ–APP interaction reminiscent of the pathogenic mechanism of prions may thus contribute to neuronal degeneration in AD.

Acceleration of Amyloid β-Peptide Aggregation by Physiological Concentrations of Calcium

Alzheimer disease is characterized by the accumulation of aggregated amyloid β-peptide (Aβ) in the brain. The physiological mechanisms and factors that predispose to Aβ aggregation and deposition are not well understood. In this report, we show that calcium can predispose to Aβ aggregation and fibril formation. Calcium increased the aggregation of early forming protofibrillar structures and markedly increased conversion of protofibrils to mature amyloid fibrils. This occurred at levels 20-fold below the calcium concentration in the extracellular space of the brain, the site at which amyloid plaque deposition occurs. In the absence of calcium, protofibrils can remain stable in vitro for several days. Using this approach, we directly compared the neurotoxicity of protofibrils and mature amyloid fibrils and demonstrate that both species are inherently toxic to neurons in culture. Thus, calcium may be an important predisposing factor for Aβ aggregation and toxicity. The high extracellular concentration of calcium in the brain, together with impaired intraneuronal calcium regulation in the aging brain and Alzheimer disease, may play an important role in the onset of amyloid-related pathology.