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Amyloidß-protein (Aß) assembly into toxic fibrillar structures is seminal in development of senile plaques, the pathological hallmark of Alzheimer's disease. Blocking this process could have a therapeutic value. ß-sheet breaker peptides (ßSBP) decrease Aß fibrillogenesis and neurotoxicity by preventing or dissolving misfolded Aß aggregates. The present study investigated the effects of ßSBPs on Aß40-related neuropathology, memory impairment in 8-armed radial maze and expression of Aß40 in brain and serum. Aß40 was injected into amygdaloid nucleus followed 8 days later by octapeptideßSBPs 15-22, 16-23 and 17-24. Aß40 was detected not only in amygdala, but also in serum. Aß40 induced cellular changes in amygdala and additionally in hippocampus. Aß40 decreased correct choices, whereas increased errors (both number of arms revisited and total number of revisits) and latency of completing the maze test. The ßSBPs decreased Aß40-induced pathological changes, memory impairment and Aß40 expression in serum. The ßSBP15-22 distinctively decreased the total errors on day 14. The present results show that octapeptide ßSBPs corrected Aß40-induced memory impairment, and support investigation of ßSBPs as a promising treatment of diseases characterized by neurodegeneration and memory impairment such as Alzheimer's disease.

Amyloid?-protein (A?) assembly into toxic fibrillar structures is seminal in development of senile plaques, the pathological hallmark of Alzheimer's disease. Blocking this process could have a therapeutic value. ?-sheet breaker peptides (?SBP) decrease A? fibrillogenesis and neurotoxicity by preventing or dissolving misfolded A? aggregates. The present study investigated the effects of ?SBPs on A?40-related neuropathology, memory impairment in 8-armed radial maze and expression of A?40 in brain and serum. A?40 was injected into amygdaloid nucleus followed 8 days later by octapeptide?SBPs 15-22, 16-23 and 17-24. A?40 was detected not only in amygdala, but also in serum. A?40 induced cellular changes in amygdala and additionally in hippocampus. A?40 decreased correct choices, whereas increased errors (both number of arms revisited and total number of revisits) and latency of completing the maze test. The ?SBPs decreased A?40-induced pathological changes, memory impairment and A?40 expression in serum. The ?SBP15-22 distinctively decreased the total errors on day 14. The present results show that octapeptide ?SBPs corrected A?40-induced memory impairment, and support investigation of ?SBPs as a promising treatment of diseases characterized by neurodegeneration and memory impairment such as Alzheimer's disease.

Amyloid beta-protein (A) assembly into toxic fibrillar structures is seminal in development of senile plaques, the pathological hallmark of Alzheimer's disease. Blocking this process could have a therapeutic value. beta-sheet breaker peptides (beta SBP) decrease A beta fibrillogenesis and neurotoxicity by preventing or dissolving misfolded A beta aggregates. The present study investigated the effects of beta SBPs on A beta 40-related neuropathology, memory impairment in 8-armed radial maze and expression of A beta 40 in brain and serum. A beta 40 was injected into amygdaloid nucleus followed 8 days later by octapeptide beta SBPs 15-22, 16-23 and 17-24. A beta 40 was detected not only in amygdala, but also in serum. A beta 40 induced cellular changes in amygdala and additionally in hippocampus. A beta 40 decreased correct choices, whereas increased errors (both number of arms revisited and total number of revisits) and latency of completing the maze test. The beta SBPs decreased A beta 40-induced pathological changes, memory impairment and A beta 40 expression in serum. The beta SBP15-22 distinctively decreased the total errors on day 14. The present results show that octapeptide beta SBPs corrected A beta 40-induced memory impairment, and support investigation of beta SBPs as a promising treatment of diseases characterized by neurodegeneration and memory impairment such as Alzheimer's disease.

Amyloid beta-protein (A) assembly into toxic fibrillar structures is seminal in development of senile plaques, the pathological hallmark of Alzheimer's disease. Blocking this process could have a therapeutic value. beta-sheet breaker peptides (beta SBP) decrease A beta fibrillogenesis and neurotoxicity by preventing or dissolving misfolded A beta aggregates. The present study investigated the effects of beta SBPs on A beta 40-related neuropathology, memory impairment in 8-armed radial maze and expression of A beta 40 in brain and serum. A beta 40 was injected into amygdaloid nucleus followed 8 days later by octapeptide beta SBPs 15-22, 16-23 and 17-24. A beta 40 was detected not only in amygdala, but also in serum. A beta 40 induced cellular changes in amygdala and additionally in hippocampus. A beta 40 decreased correct choices, whereas increased errors (both number of arms revisited and total number of revisits) and latency of completing the maze test. The beta SBPs decreased A beta 40-induced pathological changes, memory impairment and A beta 40 expression in serum. The beta SBP15-22 distinctively decreased the total errors on day 14. The present results show that octapeptide beta SBPs corrected A beta 40-induced memory impairment, and support investigation of beta SBPs as a promising treatment of diseases characterized by neurodegeneration and memory impairment such as Alzheimer's disease.

Background and purpose: Aggregates of the protein amyloid-beta (Aß) play a crucial role in the pathogenesis of Alzheimer's disease (AD). Most therapeutic approaches to AD do not target Aß, so determination of the factor(s) that facilitate aggregation and discovering agents that prevent aggregation have great potential therapeutic value. Experimental approach: We investigated ex vivo the temperature-sensitive regions of Aß1-40 (Aß40) and their interactions with octapeptides derived from sequences within Aß40 - ß-sheet breaker peptides (ßSBP) - using enzyme-linked immunosorbent assay, and dot blot and far-UV circular dichroism (CD) spectroscopy. We measured changes within the physiological limits of temperature, using antibodies targeting epitopes 1-7, 5-10, 9-14 and 17-21 within Aß40. Key results: Temperature-dependent conformational changes were observed in Aß40 at epitopes 9-14 and 17-21 at 36-38 and 36-40°C respectively. The ßSBPs 16-23 and 17-24, but not 15-22 and 18-25, could inhibit the changes. Moreover, ßSBPs 16-23 and 17-24 increased digestion of Aß40 by protease K, indicating a decreased aggregation of Aß40, whereas ßSBPs 15-22 and 18-25 did not increase this digestion. CD spectra revealed that ß-sheet formation in Aß40 at 38°C was reduced with ßSBPs 16-23 and 17-24. Conclusions and implications: The epitopes 9-14 and 17-21 are the temperature-sensitive regions within Aß40. The ßSBPs, Aß16-23 and 17-24 reversed temperature-induced ß-sheet formation, and decreased Aß40 aggregation. The results suggest that the 17-23 epitope of Aß40 is crucially involved in preventing Aß40 aggregation and consequent deposition of Aß40 in AD brain. © 2009 The British Pharmacological Society.

Background and purpose: Aggregates of the protein amyloid-beta (A beta) play a crucial role in the pathogenesis of Alzheimer's disease (AD). Most therapeutic approaches to AD do not target A beta, so determination of the factor(s) that facilitate aggregation and discovering agents that prevent aggregation have great potential therapeutic value. Experimental approach: We investigated ex vivo the temperature-sensitive regions of A beta 1-40 (A beta 40) and their interactions with octapeptides derived from sequences within A beta 40 - beta-sheet breaker peptides (beta SBP) - using enzyme-linked immunosorbent assay, and dot blot and far-UV circular dichroism (CD) spectroscopy. We measured changes within the physiological limits of temperature, using antibodies targeting epitopes 1-7, 5-10, 9-14 and 17-21 within A beta 40. Key results: Temperature-dependent conformational changes were observed in A beta 40 at epitopes 9-14 and 17-21 at 36-38 and 36-40 degrees C respectively. The beta SBPs 16-23 and 17-24, but not 15-22 and 18-25, could inhibit the changes. Moreover, beta SBPs 16-23 and 17-24 increased digestion of A beta 40 by protease K, indicating a decreased aggregation of A beta 40, whereas beta SBPs 15-22 and 18-25 did not increase this digestion. CD spectra revealed that beta-sheet formation in A beta 40 at 38 degrees C was reduced with beta SBPs 16-23 and 17-24. Conclusions and implications: The epitopes 9-14 and 17-21 are the temperature-sensitive regions within A beta 40. The beta SBPs, A beta 16-23 and 17-24 reversed temperature-induced beta-sheet formation, and decreased A beta 40 aggregation. The results suggest that the 17-23 epitope of A beta 40 is crucially involved in preventing A beta 40 aggregation and consequent deposition of A beta 40 in AD brain.

BACKGROUND AND PURPOSE: Aggregates of the protein amyloid-beta (Abeta) play a crucial role in the pathogenesis of Alzheimer's disease (AD). Most therapeutic approaches to AD do not target Abeta, so determination of the factor(s) that facilitate aggregation and discovering agents that prevent aggregation have great potential therapeutic value. EXPERIMENTAL APPROACH: We investigated ex vivo the temperature-sensitive regions of Abeta1-40 (Abeta40) and their interactions with octapeptides derived from sequences within Abeta40 -beta-sheet breaker peptides (betaSBP) - using enzyme-linked immunosorbent assay, and dot blot and far-UV circular dichroism (CD) spectroscopy. We measured changes within the physiological limits of temperature, using antibodies targeting epitopes 1-7, 5-10, 9-14 and 17-21 within Abeta40. KEY RESULTS: Temperature-dependent conformational changes were observed in Abeta40 at epitopes 9-14 and 17-21 at 36-38 and 36-40 degrees C respectively. The betaSBPs 16-23 and 17-24, but not 15-22 and 18-25, could inhibit the changes. Moreover, betaSBPs 16-23 and 17-24 increased digestion of Abeta40 by protease K, indicating a decreased aggregation of Abeta40, whereas betaSBPs 15-22 and 18-25 did not increase this digestion. CD spectra revealed that beta-sheet formation in Abeta40 at 38 degrees C was reduced with betaSBPs 16-23 and 17-24. CONCLUSIONS AND IMPLICATIONS: The epitopes 9-14 and 17-21 are the temperature-sensitive regions within Abeta40. The betaSBPs, Abeta16-23 and 17-24 reversed temperature-induced beta-sheet formation, and decreased Abeta40 aggregation. The results suggest that the 17-23 epitope of Abeta40 is crucially involved in preventing Abeta40 aggregation and consequent deposition of Abeta40 in AD brain.