Content area
Abstract
As of 2022, more than 1 in 10 Americans who are 65 years of age or older suffer from AD-related dementia, and a long-term, multinational study spanning 3 decades revealed that the incidence of Alzheimer’s Disease (AD) -related dementia diagnosis has more than doubled within the time range in which the study was conducted.[1-3] The increased prevalence will ultimately put an immense strain on healthcare systems at a global scale; however, despite the vast research to inform how the disease is initiated and spread across the brain, little improvements on therapeutic solutions have been made. Conflicting observations of otherwise potential AD biomarkers, namely Aβ42 and tau plaques, in animals excluding humans, studying the pathogenic transformation in nonhuman primates and other mammals could leave an incomplete picture of a disease model.
The works described here sought to eliminate the discrepancy between animal models and humans with respect to modeling AD from its earliest manifestation by using brain organoids and to elucidate disease-relevant biopolymer associations that result in AD-linked paracrystalline assemblies. Organoids are an emerging tool that could mimic biological functions of their designated target organ and could be derived from human somatic cells, retaining all of the human donor’s genes. This full genetic retention makes organoids a promising modeling tool which could bridge the gap between animal and human studies. Brain organoids were grown alongside protease- and detergent-resistant AD brain tissue-derived isolates, resulting in both genotypic and phenotypic alterations that mirrored AD-like changes in the brain. Further analysis of these isolates revealed that there were strong mutualistic associations between Aβ42 and tau, which further support the amyloid cascade hypothesis.
Lastly, the observations made in assemblies consisting of minimal Aβ42 and tau models revealed that cross-strand peptide associations could be modulated by introducing small amounts of mature assemblies as seed. The overall interactions are also highly sensitive to structural intricacies within the seed. Similarly, while charge complementarity is a main driver of cooperative, template-directed peptide-DNA interactions, the charge-ordering of a DNA template could dictate the entire assembly pathway, which produced distinct paracrystalline morphologies.
