Therapeutic approaches targeting betta-amyloid cascade in Alzheimers disease

Alzheimer’s disease (AD) is the most common cause of dementia, affecting nearly fi ve million patients in the USA and 20 million worldwide. The β-amyloid (Aβ) cascade hypothesis maintains that accumulation of Aβ peptide is a critical event in the early pathogenesis of AD. This lecture will review key steps of Aβ metabolism and their disturbances leading to build-up of Aβ in the AD brain. Development of therapeutic approaches targeting Aβ cascade will be subsequently discussed. They include passive and active immunization against Aβ, inhibitors of β and γ secretases, RAGE inhibitors, β-sheet breakers and approaches targeting the apolipoprotein E (apoE). ApoE is a critical factor promoting Aβ deposition in the brain and affecting its clearance. The magnitude of the apoE/Aβ interaction is isoform specifi c, providing an explanation for the linkage between the apoE4 allele and an increased risk of sporadic AD. Our laboratory has demonstrated that blocking the apoE/Aβ binding with synthetic peptide-Aβ12-28P, which mimics the apoE binding site on Aβ, reduces the burden of vascular and parenchymal Aβ deposits in AD transgenic mice and prevents them from developing a memory defi cit. Ongoing research pursues development of peptidomimetic derivatives of Aβ12-28P with improved therapeutic effi cacy and biostability with the aim to obtain a lead therapeutic compound for clinical investigations. Support: Dorothy D. Eweson Lectureship on the Advances in Aging Research, grants AG24847, AG31221