AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway

This study published in Brain Sciences evaluated the effects of Dihexa in the APP/PS1 transgenic model — one of the most widely used murine models for Alzheimer's disease, which expresses human mutations in the amyloid precursor protein (APP) and presenilin-1 (PS1) genes, leading to progressive accumulation of beta-amyloid plaques and cognitive decline.

APP/PS1 mice treated with Dihexa showed significant restoration of spatial learning and memory as assessed by the Morris water maze and novel object recognition test. The performance of treated animals approached that of wild-type controls, indicating substantial functional recovery despite the underlying amyloid pathology.

At the molecular level, Dihexa activated the PI3K/AKT signaling pathway in the hippocampus of treated mice. This pathway is crucial for neuronal survival, synaptic plasticity, and resistance to oxidative stress. AKT activation (also known as protein kinase B) promotes phosphorylation of anti-apoptotic substrates and stimulates the synthesis of synaptic proteins. Additionally, significant reduction in neuroinflammation was observed, with decreased markers of microglial activation and pro-inflammatory cytokines in brain tissue.

This study is particularly relevant for validating Dihexa in a genetic model of Alzheimer's disease (more predictive than acute pharmacological models such as scopolamine) and for identifying the PI3K/AKT pathway as an additional mediator of neuroprotective effects, complementing the previously described HGF/c-Met mechanism. The results reinforce Dihexa's potential as a therapeutic candidate for neurodegenerative diseases with a cognitive impairment component.