An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice
Alzheimer’s disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid β (Aβ) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti‐amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed. The efficacy of the designed peptide, R8‐Aβ(25–35), on amyloid reduction and the improvement of cognitive functions were evaluated using APP/PS1 double transgenic mice. Daily intranasal administration of PEI‐conjugated R8‐Aβ(25–35) peptide significantly reduced Aβ amyloid accumulation and ameliorated the memory deficits of the transgenic mice. Intranasal administration is a feasible route for peptide delivery. The modular design combining polyR and aggregate‐forming segments produced a desirable therapeutic effect and could be easily adopted to design therapeutic peptides for other proteinaceous aggregate‐associated diseases.
Alzheimer’s disease (AD) is the most common neurodegenerative disease that causes dementia across multiple cognitive domains. Its incidence increases significantly with age and doubles every 5 years among the geriatric population ≧ 65 years of age. Despite remarkable scientific advancement and the vast resources invested in drug development, no effective therapy is currently available for AD. Thus, it is listed as one of the major unmet medical needs worldwide. Peptide drugs have been used with consistent benefits for many years and have advantages over small molecules, such as higher potency and fewer off‐target side effects (Craik et al, 2013). In addition, the properties of easy customization and synthesis under a well‐controlled environment make peptides excellent candidates for AD drug development. Neurodegenerative diseases encompass a heterogeneous group of neurological diseases characterized by synoptic and neuronal losses caused by multiple factors. Misfolded proteinaceous aggregates which exist in a variety of these diseases besides AD, including Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, are considered one of them, and may cause or contribute to these diseases through their prionlike property (Kim & Holtzman, 2010; de Calignon et al, 2012; Luk et al, 2012; Smethurst et al, 2016). In spite of the difference in the constituent proteins and complexity of assembly mechanism, the proteinaceous aggregates across these diseases share common structural conformations such as a β‐sheet conformation in the backbone (Funke & Willbold, 2012). This provides the basis for a rational design of therapeutic peptides for these misfolded aggregate‐associated diseases by applying a universal principle to reverse the process of formation. (EMBO Mol Med. 2017 May; 9(5): 703–715.)