Beta-sheet breaker peptide prevents Abeta-induced spatial memory impairments with partial reduction of amyloid deposits.

Current evidence supports the notion that beta-amyloid deposits or Abeta intermediates may be responsible for the pathogenesis in Alzheimer's disease (AD) patients. In the present work, we have assessed the neuroprotective effect of the chronic intraperitoneal administration of a five-amino-acid beta-sheet breaker peptide (iAbeta5p) on the rat behavioral deficit induced by the intrahippocampal Abeta-fibrils injection. At 1 month after the injection, animals showed a partial reduction of the amyloid deposits formed and a decreased astrocytic response around the injection site. More importantly, we report that following the iAbeta5p treatment, hippocampal-dependent spatial learning paradigms, including the standard Morris water maze and a working memory analysis, showed a significant prevention from impairments induced by Abeta deposits in the dorsal hippocampus. Thus, it is possible that a noninvasive treatment such as the one presented here with beta-sheet breaker peptides may be used as a potential therapy for AD patients.

A human prion protein peptide (PrP(59-91)) protects against copper neurotoxicity.

Human cellular prion protein (PrP(C)) is involved in several neurodegenerative disorders; however, its normal function is unknown. We report here that a synthetic peptide corresponding to the four-octarepeat sequence of the PrP(C) (PrP(59-91)) protects hippocampal neurons against copper neurotoxic effects in vivo. Using a rat bilateral intrahippocampal injection model, we found that PrP(59-91) protects against copper-induced neurotoxicity, including a recovery in spatial learning performance and a reduced neuronal cell loss and astrogliosis. Previous studies from our laboratory indicated that a tryptophan (Trp) residue plays a key role in the reduction of copper(II) to copper(I); therefore several PrP(59-91) fragments lacking histidine (His) and Trp residues were tested for their capacity to protect from copper toxicity. A PrP(59-91) peptide lacking His residue shows as much neuroprotection as the native peptide; however, PrP(59-91) without Trp residues only partially protected against copper toxicity. The neuroprotective effect not only occurs with PrP(59-91), in fact a full neuroprotection was also observed using just one octamer of the N-terminal region of prion protein. We conclude that the N-terminal tandem octarepeat of the human PrP(C) protects neurons against copper toxicity by a differential contribution of the binding (His) and reducing (Trp) copper activities of PrP(59-91). Our results are consistent with the idea that PrP(C) function is related to copper homeostasis.

Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is probably caused by the cytotoxic effect of the amyloid beta-peptide (Abeta). We report here molecular changes induced by Abeta, both in neuronal cells in culture and in rats injected in the dorsal hippocampus with preformed Abeta fibrils, as an in vivo model of the disease. Results indicate that in both systems, Abeta neurotoxicity resulted in the destabilization of endogenous levels of beta-catenin, a key transducer of the Wnt signaling pathway. Lithium chloride, which mimics Wnt signaling by inhibiting glycogen synthase kinase-3beta promoted the survival of post-mitotic neurons against Abeta neurotoxicity and recovered cytosolic beta-catenin to control levels. Moreover, the neurotoxic effect of Abeta fibrils was also modulated with protein kinase C agonists/inhibitors and reversed with conditioned medium containing the Wnt-3a ligand. We also examined the spatial memory performance of rats injected with preformed Abeta fibrils in the Morris water maze paradigm, and found that chronic lithium treatment protected neurodegeneration by rescuing beta-catenin levels and improved the deficit in spatial learning induced by Abeta. Our results are consistent with the idea that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and indicate that lithium or compounds that mimic this signaling cascade may be putative candidates for therapeutic intervention in Alzheimer's patients.