Developing Trojan horses to induce, diagnose and suppress Alzheimer's pathology

There are many obstacles impeding the Alzheimer's disease (AD) research. For instance, its early diagnosis to identify individuals at risk has not been successful so far. AD animal models cannot be created without genetic pre-disposition or surgical manipulation. Single gene/protein delivery has so far failed to achieve significant clinical improvements in multifactorial AD. We hypothesize that the blood-brain barrier (BBB) penetration issues are the major obstacle in the development of current Alzheimer's causative, diagnostic, and multi-targeted therapeutic probes, and partly the cause of the failure of more than 99% of intervention trials. To overcome this problem, shuttle peptides or monoclonal antibodies for receptors on BBB can act as molecular Trojan horses to transport the fused novel classes of re-engineered AD causative agents, diagnostic probes, or multiple function neurovascular medicines across the BBB via receptor-mediated transport to cause, diagnose, or improve the AD phenotype, respectively. Here, we propose the design of such Trojan horses, comprising three essential components that could (i) reverse Aβ amyloidosis, (ii) clear liberated Aβ, and (iii) improve angiogenesis or endothelial metabolic dysfunction, besides alleviating the inflammation, to eventually enhance neuronal health, cerebral blood flow, and cognitive function. Such Trojan horses can aid in AD research by diagnosing Aβ-oligomers at earlier stages, creating improved animal models by exposing transgenic animals to amyloid-inducing agents, and allowing treatment by novel neurovascular medicines.