Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 34, Issue 3, Pages 609-620Publisher
IOS PRESS
DOI: 10.3233/JAD-121792
Keywords
Age; Alzheimer's disease; amyloid; limbic system; mouse; plaques; treatment
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Funding
- Technology Transfer Fund of the Research Center Julich
- NIH [P30 NS47466]
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One of the characteristic pathological hallmarks of Alzheimer's disease (AD) is neuritic plaques. The sequence of events leading to deposition of amyloid-beta (A beta) peptides in plaques is not clear. Here we investigate the effects of D3, an A beta oligomer directed D-enantiomeric peptide that was obtained from a mirror image phage display selection against monomeric or small oligomeric forms of A beta(42), on A beta deposition in aged A beta PP/PS1 double transgenic AD-model mice. Using Alzet minipumps, we infused the brains of these AD model mice for 8 weeks with FITC-labeled D3, and examined the subsequent changes in pathology and cognitive deficits. Initial cognitive deficits are similar comparing control and D3-FITC-treated mice, but the treated mice show a significant improvement on the last day of testing. Further, we show that there is a substantial reduction in the amount of amyloid deposits in the animals treated with D3-FITC, compared to the control mice. Finally, the amount of activated microglia and astrocytes surrounding A beta deposits is dramatically reduced in the D3-FITC-treated mice. Our findings demonstrate that treatments with the high affinity A beta(42) oligomer binding D-enantiomeric peptide D3 significantly decrease A beta deposits and the associated inflammatory response, and improve cognition even when applied only at late stages and high age. Together, this suggests that the treatment reduces the level of A beta peptide in the brains of A beta PP/PS1 mice, possibly by increasing A beta outflow from the brain. In conclusion, treatments with this D-peptide have great potential to be successful in AD patients.
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