Potential of blocking apoE/A in Alzheimer's disease

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The accumulation of amyloid-beta (A) peptides is an important stage in the early pathogenesis of Alzheimer's disease (AD), and the binding of A peptides to apolipoprotein E (apoE) has a key role in the sequestration of A in the CNS and in the formation of A deposits. Hence, blocking the apoE/A interaction might constitute a novel therapeutic approach for AD. Now, researchers in New York, NY, have demonstrated the potential of this approach in vivo.
A number of studies have demonstrated that short synthetic peptides corresponding to the apoE binding site on the A peptide can bind to human apoE and block its effect on A accumulation. Sadowski et al. developed a blood–brain-barrier-permeable, nontoxic, nonfibrillogenic synthetic peptide, A12–28P, which binds apoE with high affinity. Systemic administration of A12–28P to two transgenic mouse models of AD resulted in marked reductions in A plaque and cerebral amyloid angiopathy burdens, along with a reduction in the absolute A level in the brain. Behavioral testing with the radial arm maze demonstrated that A12–28P treatment prevented memory deficit; at age 17–18 months, transgenic AD mice given A12–28P performed comparably to wild-type mice, whereas placebo-administered transgenic AD mice showed significantly worse performance than wild-type or A12–28P-treated AD mice (P <0.001 style="font-weight: bold; font-style: italic;" size="1">Sadowski MJ et al. (2006) Blocking the apolipoprotein E/amyloid- interaction as a potential therapeutic approach for Alzheimer's disease. Proc Natl Acad Sci USA 103: 18787–18792