Our main hypothesis is that a therapeutic agent blocking the interaction between apolipoprotein E and B-amyloid will be effective in reducing and preventing 6-amyloid ( AB ) related pathology of Alzheimer's disease (AD).The B-amyloid ( AB ) cascade hypothesis maintains that accumulation of the AB peptide constitutes a critical event in the early pathogenesis of AD. An excess of AB assembles into toxic oligomers and subsequently into deposits in the brain's parenchyma and in walls of vessels producing cerebral amyloid angiopathy (CAA).The direct binding between AB and apolipoprotein E (apoE) has been identified as an important factor promoting the deposition of AB in the CMS and regulating its clearance across the blood-brain-barrier (BBB).The magnitude of apoE/AB interaction appears to be isoform specific, providing one explanation for the linkage between the apoE4 allele and an increased risk of sporadic AD. We have demonstrated that blocking the apoE/AB binding with a synthetic peptide - AB 12-28P, that mimics the apoE binding site on AB and was modified for in vivo application, reduces the burden of parenchynal AB deposits and CAA, as well as preventing memory impairment in AD transgenic (Tg) mice (Sadowski et al. AJP, 2004;165:937;Sadowski et al., PNAS, 2006;103:18787). In contrast, anti- AB vaccination approaches prevent only parenchymal AB deposition without affecting the CAA burden. In addition, vaccination appears to increase the risk of perivascular hemorrhages which were absent in AD Tg animals treated with AB 12-28P. In this grant proposal, we are planning to develop non-toxic peptidomimetic antagonists of the apoE/ AB interaction which will be based on the AB 12-28 sequence. The objectives are to improve therapeutic efficacy, BBB penetration, and biostability. Due to the inherent biomimetic character of peptidomimetics, their resistance to degradation, and ease of chemical modification, this strategy has been successfully employed in the past to develop a number of therapeutically promising compounds. Selected peptidomimetic compounds will be tested in AD Tg models including those expressing differing human apoE isoforms. This will be done to predict the therapeutic response in carriers of the various human apoE isoforms. To determine whether this form of therapy can lead to a reduction of already existing AB deposits we will perform in vivo imaging of AB plaques in AD Tg mice using transcranial two-photon microscopy. Although the primary goal of blocking the apoE/ AB interaction is to prevent AB fibrillar assembly and deposition there are also several other potential benefits of this approach which we investigate in this application. Thus, we will determine the effect of blocking the apoE/ AB interaction on AB and apoE clearance across the BBB, the equilibrium between AB oligomers and fibril formation, and intraneuronal accumulation of apoE/ AB complexes. The overall goal of this proposal is to bring this novel therapeutic approach closer to clinical studies and to identify a lead peptidomimetic compound, which could be further developed for safe, long-term application in humans

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Refolo, Lorenzo
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New York University
Schools of Medicine
New York
United States
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Asuni, Ayodeji A; Pankiewicz, Joanna E; Sadowski, Martin J (2014) Reply: To PMID 24687915. Ann Neurol 76:630-1
Pankiewicz, Joanna E; Guridi, Maitea; Kim, Jungsu et al. (2014) Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice. Acta Neuropathol Commun 2:75
Kuszczyk, Magdalena A; Sadowski, Martin J; Antkiewicz-Michaluk, Lucyna et al. (2014) 1MeTIQ provides protection against Aβ-induced reduction of surface expression of synaptic proteins and inhibits H₂O₂-induced oxidative stress in primary hippocampal neurons. Neurotox Res 25:348-57
Asuni, Ayodeji A; Guridi, Maitea; Pankiewicz, Joanna E et al. (2014) Modulation of amyloid precursor protein expression reduces β-amyloid deposition in a mouse model. Ann Neurol 75:684-99
Kuszczyk, Magdalena A; Sanchez, Sandrine; Pankiewicz, Joanna et al. (2013) Blocking the interaction between apolipoprotein E and Aβ reduces intraneuronal accumulation of Aβ and inhibits synaptic degeneration. Am J Pathol 182:1750-68
Duszczyk, Malgorzata; Kuszczyk, Magdalena; Guridi, Maitea et al. (2012) In vivo hippocampal microdialysis reveals impairment of NMDA receptor-cGMP signaling in APP(SW) and APP(SW)/PS1(L166P) Alzheimer's transgenic mice. Neurochem Int 61:976-80
Sadowski, Martin J (2010) Circulating angiogenic cells and Alzheimer's disease: contribution of the bone marrow to the pathogenesis of the disease. J Alzheimers Dis 19:1241-3
Wisniewski, Thomas; Sadowski, Martin (2008) Preventing beta-amyloid fibrillization and deposition: beta-sheet breakers and pathological chaperone inhibitors. BMC Neurosci 9 Suppl 2:S5