TARGETING AΒ PRODUCTION WITH A CELL PENETRATING CIS-Γ-AMINO-L-PROLINE DERIVED PEPTIDE: EVIDENCE FROM IN VITRO STUDIES AND APP/PS1 MICE

Alzheimer’s disease (AD) is characterized by two major pathological hallmarks: the accumulation of hyperphosphorylated tau protein, which forms neurofibrillary tangles, and the deposition of amyloid plaques largely composed of amyloid-β (Aβ) peptides. Evidence from familial cases implicates alterations in the proteolytic processing of the amyloid precursor protein (APP), leading to increased generation of Aβ. This peptide arises from the sequential amyloidogenic cleavage of APP by β-secretase (BACE1) and γ-secretase, and current therapeutic strategies predominantly focus on limiting Aβ production or enhancing its clearance. Recent FDA-approved monoclonal antibodies targeting Aβ have shown some clinical promise but continue to raise concerns regarding safety, efficacy, and accessibility. Peptide-based therapeutics represent an alternative approach, but their application is frequently restricted by limited proteolytic stability and insufficient membrane permeability.
Cell-penetrating peptides (CPPs) circumvent several of these limitations by providing efficient and low-toxicity delivery across diverse cell types. In this study, a unique CPP library composed of cis-γ-amino-L-proline-based γ-peptide oligomers was screened. These molecules were functionalized at the α-amine of proline with substituents mimicking natural amino acid side chains. The objective was to identify candidates capable of reducing Aβ production in primary cortical neurons through modulation of BACE1 activity. From this screen, γ-peptide 33 (P33) emerged as a promising molecule. Subsequent evaluation in the APP/PS1 mouse model demonstrated that P33 treatment reduced amyloid burden, improved performance in novel object recognition tasks, and exhibited favorable biocompatibility. Together, these findings suggest that P33 offers potential as a novel therapeutic candidate aimed at mitigating Aβ pathology in AD.