Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease

MJ Sadowski, J Pankiewicz… - Proceedings of the …, 2006 - National Acad Sciences
MJ Sadowski, J Pankiewicz, H Scholtzova, PD Mehta, F Prelli, D Quartermain, T Wisniewski
Proceedings of the National Academy of Sciences, 2006National Acad Sciences
The amyloid-β (Aβ) cascade hypothesis of Alzheimer's disease (AD) maintains that
accumulation of Aβ peptide constitutes a critical event in the early disease pathogenesis.
The direct binding between Aβ and apolipoprotein E (apoE) is an important factor implicated
in both Aβ clearance and its deposition in the brain's parenchyma and the walls of
meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the
effect of blocking the apoE/Aβ interaction in vivo as a potential novel therapeutic target for …
The amyloid-β (Aβ) cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of Aβ peptide constitutes a critical event in the early disease pathogenesis. The direct binding between Aβ and apolipoprotein E (apoE) is an important factor implicated in both Aβ clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/Aβ interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, we have developed Aβ12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length Aβ. Aβ12-28P binds with high affinity to apoE, preventing its binding to Aβ, but has no direct effect on Aβ aggregation. Aβ12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of Aβ plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of Aβ in two AD transgenic mice models. The treatment did not affect the levels of soluble Aβ fraction or Aβ oligomers, indicating that inhibition of the apoE/Aβ interaction in vivo has a net effect of increasing Aβ clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with Aβ12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD.
National Acad Sciences