title: Treatment with D3 removes amyloid deposits, reduces inflammation, and improves cognition in aged AβPP/PS1 double transgenic mice.
abstract: One of the characteristic pathological hallmarks of Alzheimer's disease (AD) is neuritic plaques. The sequence of events leading to deposition of amyloid-β (Aβ) peptides in plaques is not clear. Here we investigate the effects of D3, an Aβ oligomer directed D-enantiomeric peptide that was obtained from a mirror image phage display selection against monomeric or small oligomeric forms of Aβ42, on Aβ deposition in aged AβPP/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 Aβ deposits is dramatically reduced in the D3-FITC-treated mice. Our findings demonstrate that treatments with the high affinity Aβ42 oligomer binding D-enantiomeric peptide D3 significantly decrease Aβ 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 Aβ peptide in the brains of AβPP/PS1 mice, possibly by increasing Aβ outflow from the brain. In conclusion, treatments with this D-peptide have great potential to be successful in AD patients.
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. vangroen@uab.edu
authors.forename: Thomas
authors.initials: T
authors.lastname: van Groen
authors.forename: Inga
authors.initials: I
authors.lastname: Kadish
authors.forename: Susanne Aileen
authors.initials: SA
authors.lastname: Funke
authors.forename: Dirk
authors.initials: D
authors.lastname: Bartnik
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000235:genetics*; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000008:administration & dosage* / Q000235:genetics; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D053764:Presenilin-1 / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D016564:Amyloid beta-Protein Precursor; C534952:D3 peptide; D009842:Oligopeptides; C508853:PSEN1 protein, human; D053764:Presenilin-1