Targeting Alzheimer’s disease with multimodal polypeptide-based nanoconjugates

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.

Protein Aggregation in a Nutshell: The Splendid Molecular Architecture of the Dreaded Amyloid Fibrils

The recent high-resolution structures of amyloid fibrils show that the organization of peptide segments into amyloid aggregate architecture is a general process, though the morphology is more complex and intricate than suspected previously. The amyloid fibrils are often cytotoxic, accumulating as intracellular inclusions or extracellular plaques and have the ability to interfere with cellular physiology causing various cellular malfunctions. At the same time, the highly ordered amyloid structures also present an opportunity for nature to store and protect peptide chains under extreme conditions – something that might be used for designing storage, formulation, and delivery of protein medications or for contriving bio-similar materials of great resistance or structure-ordering capacity. Here we summarize amyloid characteristics; discussing the basic morphologies, sequential requirements and 3D-structure that are required for the understanding of this newly (re)discovered protein structure – a prerequisite for developing either inhibitors or promoters of amyloid-forming processes

Bifunctional fluorescent probes for detection of amyloid aggregates and reactive oxygen species

Protein aggregation into amyloid deposits and oxidative stress are key features of many neurodegenerative disorders including Parkinson's and Alzheimer's disease. We report here the creation of four highly sensitive bifunctional fluorescent probes, capable of H 2 O 2 and/or amyloid aggregate detection. These bifunctional sensors use a benzothiazole core for amyloid localization and boronic ester oxidation to specifically detect H 2 O 2 . We characterized the optical properties of these probes using both bulk fluorescence measurements and single-aggregate fluorescence imaging, and quantify changes in their fluorescence properties upon addition of amyloid aggregates of α-synuclein and pathophysiological H 2 O 2 concentrations. Our results indicate these new probes will be useful to detect and monitor neurodegenerative disease.

PEG modified graphene oxide loaded with EALYLV peptides for inhibiting the aggregation of hIAPP associated with type-2 diabetes

Human islet amyloid polypeptide (hIAPP) was found as amyloid aggregate deposits in the pancreatic islets of patients with type-2 diabetes and studies showed that insulin and its derivatives were the potent inhibitors of hIAPP aggregation.