b-Amyloid protein (bAP) is thought to cause neuronal loss in Alzheimer’s disease (AD). Applied to neurons in culture, bAP induces neuronal death and hyperphosphorylation of tau protein, which forms neurofibrillary tangles (NFTs) in AD brains. Neurons also undergo rapid apoptotic death following reactivation of a mitotic cycle. However, the molecular events that determine the fate of neurons challenged with bAP (apoptotic death, formation of NFTs and survival) are unclear. We discuss a scenario for the pathogenesis of AD. This links bAP-induced changes to the Wnt signaling pathway that promotes proliferation of progenitor cells and directs cells into a neuronal phenotype during brain development. We propose that bAP-mediated facilitation of mitogenic Wnt signaling activates unscheduled mitosis in differentiated neurons. Furthermore, late downregulation of Wnt signaling by bAP might lead to NFT formation. We propose that drugs that both inhibit the cell cycle and rescue Wnt activity could provide novel AD therapeutics.
THE WNT PATHWAY, CELL-CYCLE ACTIVATION AND BETA-AMYLOID: NOVEL THERAPEUTIC STRATEGIES IN ALZHEIMER'S DISEASE / Caricasole, A; Copani, A; Caruso, Alessandra Sebastiana Maria; Caraci, F; Iacovelli, Luisa; Sortino, Ma; Terstappen, Gc; Nicoletti, Ferdinando. - In: TRENDS IN PHARMACOLOGICAL SCIENCES. - ISSN 0165-6147. - 24:(2003), pp. 233-238. [10.1016/S0165-6147(03)00100-7]
THE WNT PATHWAY, CELL-CYCLE ACTIVATION AND BETA-AMYLOID: NOVEL THERAPEUTIC STRATEGIES IN ALZHEIMER'S DISEASE
CARUSO, Alessandra Sebastiana Maria;IACOVELLI, LUISA;NICOLETTI, Ferdinando
2003
Abstract
b-Amyloid protein (bAP) is thought to cause neuronal loss in Alzheimer’s disease (AD). Applied to neurons in culture, bAP induces neuronal death and hyperphosphorylation of tau protein, which forms neurofibrillary tangles (NFTs) in AD brains. Neurons also undergo rapid apoptotic death following reactivation of a mitotic cycle. However, the molecular events that determine the fate of neurons challenged with bAP (apoptotic death, formation of NFTs and survival) are unclear. We discuss a scenario for the pathogenesis of AD. This links bAP-induced changes to the Wnt signaling pathway that promotes proliferation of progenitor cells and directs cells into a neuronal phenotype during brain development. We propose that bAP-mediated facilitation of mitogenic Wnt signaling activates unscheduled mitosis in differentiated neurons. Furthermore, late downregulation of Wnt signaling by bAP might lead to NFT formation. We propose that drugs that both inhibit the cell cycle and rescue Wnt activity could provide novel AD therapeutics.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.