Targeting Alzheimer's disease with multimodal polypeptide-based nanoconjugates
Creators
- 1. Polymer Therapeutics Lab., Centro de Investigación Príncipe Felipe (CIPF), Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain.
- 2. Grupo de Investigación FRESHAGE, Departamento de Fisiología, Facultad de Medicina, Univ.. Valencia, CIBERFES-ISCIII, INCLIVA, Av. Blasco Ibáñez 15, 46010 Valencia, Spain.
- 3. Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, Univ. València, CIBERNED, 46980 Valencia, Spain AND Predepartamental Unit of Medicine, Faculty of Health Sciences, Univ. Jaume I, 12071 Castelló de la Plana, Spain.
- 4. Departamento de Psicología y Sociología, Facultad de Ciencias Sociales y Humanas, Univ. Zaragoza, Teruel, Spain.
- 5. Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Univ. Valencia, Valencia, Spain.
- 6. Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, Univ. València, CIBERNED, 46980 Valencia, Spain.
Description
Alzheimer's disease (AD), the most prevalent form of dementia, remains incurable mainly due to our failings in the search for effective pharmacological strategies. Here, we describe the development of targeted multimodal polypeptide-based nanoconjugates as potential AD treatments. Treatment with polypeptide nanoconjugates bearing propargylamine moieties and bisdemethoxycurcumin or genistein afforded neuroprotection and displayed neurotrophic effects, as evidenced by an increase in dendritic density of pyramidal neurons in organotypic hippocampal culture. The additional conjugation of the Angiopep-2 targeting moiety enhanced nanoconjugate passage through the blood-brain barrier and modulated brain distribution with nanoconjugate accumulation in neurogenic areas, including the olfactory bulb. Nanoconjugate treatment effectively reduced neurotoxic β amyloid aggregate levels and rescued impairments to olfactory memory and object recognition in APP/PS1 transgenic AD model mice. Overall, this study provides a description of a targeted multimodal polyglutamate-based nanoconjugate with neuroprotective and neurotrophic potential for AD treatment.
Files
Duro etal_SciAdv_2021_published.pdf
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