β-sheet breaker peptide prevents Aβ-induced spatial memory impairments with partial reduction of amyloid deposits

Abstract

Current evidence supports the notion that b-amyloid deposits or Ab 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 b-sheet breaker peptide (iAb5p) on the rat behavioral deficit induced by the intrahippocampal Ab-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 iAb5p treatment, hippocampaldependent spatial learning paradigms, including the standard Morris water maze and a working memory analysis, showed a significant prevention from impairments induced by Ab deposits in the dorsal hippocampus. Thus, it is possible that a noninvasive treatment such as the one presented here with b-sheet breaker peptides may be used as a potential therapy for AD patients. Molecular Psychiatry (2004) 9, 953-961.

Hyperforin prevents β-amyloid neurotoxicity and spatial memory impairments by disaggregation of Alzheimer's amyloid-β-deposits

“…Different degrees of astrocyte reactivity were observed by GFAP immunostaining, after the animals were injected with Ab fibrils alone, they presented a strong glial reaction with the presence of classical appearance of hypertrophic astrocytes. 16 Thus, at least until 18 days after coinjection of HYP plus Ab, the decrease of the reactive astrocytes was correlated with the protection of the granular cell layer loss. On the other hand, the microglial activation was analyzed, with the idea to associate it to a proinflammatory process.…”

“…The analysis of the behavioral performance showed that animals injected with Ab had the highest latency values (black circles), in accordance with the neurotoxic effects of Ab. 16 The animals injected with Ab and HYP present significantly lower escape latency values than animals injected with Ab (Figure 3a), indicating that HYP was able to reduce the cognitive impairment on spatial memory performance induced by Ab. In contrast, animals injected with aCSF or HYP did not show significant difference in their escape latency values mainly during the second week of training (Figures 3a and 4a), suggesting that HYP neither induces spatial learning impairments nor enhances the cognitive status of the rat is also the case for the animals injected with OHP-Gal or OHP-Li (Figure 3c and e).…”

“…Upon completion of the trials the rats were removed from the maze, dried and returned to its cage. Water (50 cm deep) was maintained at 19-211C, for details see Chacon et al 16 Perfusion and fixation Animals were anesthetized with Equitesin (3.5 ml/kg i.p.) and injected with heparin (4 USP/kg, i.p.)…”

“…In this context, several substances are known to inhibit Ab fibrillogenesis in vitro, including laminin, 6,8 melatonin, 9 nordihydroguaiaretic acid, 10 polyphenols, 11 site-directed monoclonal antibodies, 12 a1-antichymotrypsin, 13 Ginkgo biloba extract, 14 type IV collagen 15 and b-sheet breaker peptides. 16 Nevertheless, an effective therapeutic approach that interferes directly with the neurodegenerative process in AD is eagerly awaited.…”

“…The injections were administered into the hippocampus to induce the formation of b-amyloid deposits and the spatial learning acquisition was evaluated using the Morris water maze protocol. 16 After the behavioral studies were finished, a histological analysis of the hippocampal region was performed, to evaluate amyloid deposition, the reactive astrocytes and microglia around the injection site.…”