Tackling amyloidogenesis in Alzheimer's disease with A2V variants of Amyloid-?.

ABSTRACT: We developed a novel therapeutic strategy for Alzheimer's disease (AD) exploiting the properties of a natural variant of Amyloid-? (A?) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type A?, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (A?1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [A?1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from A? toxicity. Preclinical studies in AD mouse models showed that short-term treatment with A?1-6A2VTAT(D) inhibits A? aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the A?A2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with A?1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase A? production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics.

SUBMITTER: Di Fede G 

PROVIDER: S-EPMC4750079 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other