Altered Amyloid Precursor Protein (APP) processing and Aβ production have long been recognized as major factors in the cognitive decline associated with both Alzheimer’s Disease (AD) and HIV-Associated Neurocognitive Disorders (HAND). However, recent studies show that a linear link between β-amyloid seeding and disease progression - as proposed in the original “amyloid cascade hypothesis”- is an over-simplified explanation for these complex disorders. Events leading to APP maturation and processing rely on sophisticated molecular machinery that regulates its trafficking, modification, and cleavage. Therefore, molecular tools able to precisely affect these processes represent a powerful approach to relieve the burden of these devastating disorders.

Building on their initial observations concerning overlapping trafficking behavior of APP and US9 (a Herpes Simplex Virus transport protein), the Meucci lab designed several US9-based molecular tools able to manipulate APP processing by either direct or indirect modalities. Available data show that these US9-based molecular tools are capable of modifying APP trafficking and processing, resulting in reduced APP β-cleavage and amyloidogenic load. Additionally, soluble αAPP fragments with neuroprotective and neurotrophic properties are released from transduced cells. This novel approach, which exploits the molecular properties of a viral protein to achieve specific effector engagement, establishes US9 as a powerful molecular driver for functional neuronal targeting thus paving the way to new therapeutics for pathologies implicating APP misprocessing, like AD and HAND.