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Misfolded A & beta; is involved in the progression of Alzheimers disease (AD). However, the role of its polymorphic variants or conformational strains in AD pathogenesis is not fully understood. Here, we study the seeding properties of two structurally defined synthetic misfolded A & beta; strains (termed 2F and 3F) using in vitro and in vivo assays. We show that 2F and 3F strains differ in their biochemical properties, including resistance to proteolysis, binding to strain-specific dyes, and in vitro seeding. Injection of these strains into a transgenic mouse model produces different pathological features, namely different rates of aggregation, formation of different plaque types, tropism to specific brain regions, differential recruitment of A & beta;(40)/A & beta;(42) peptides, and induction of microglial and astroglial responses. Importantly, the aggregates induced by 2F and 3F are structurally different as determined by ssNMR. Our study analyzes the biological properties of purified A & beta; polymorphs that have been characterized at the atomic resolution level and provides relevant information on the pathological significance of misfolded A & beta; strains., Funding Agencies|Junta de Andaluca Consejera de Economa y Conocimiento of Spain co-financed by Programa Operativo FEDER [P18-RT-2233, Z01-DK029061-14, U42OD11158]; National Disease Research Interchange (NDRI); National Institutes of Health [R56AG061878, RF1AG059321]; Alzheimers Association [AARGD-18-566576]; Health Institute Carlos II (ISCIII) of Spain; European Union; Junta de Andalucia Consejeria de Economia y Conocimiento of Spain; Programa Operativo FEDER 2014-2020 [P18-RT-2233, UMA18-FEDERJA-211]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health [Z01-DK029061-14]; NIH [U42OD11158]

Many efforts targeting amyloid-beta (A beta) plaques for the treatment of Alzheimers Disease thus far have resulted in failures during clinical trials. Regional and temporal heterogeneity of efficacy and dependence on plaque maturity may have contributed to these disappointing outcomes. In this study, we mapped the regional and temporal specificity of various anti-A beta treatments through high-resolution light-sheet imaging of electrophoretically cleared brains. We assessed the effect on amyloid plaque formation and growth in Thy1-APP/PS1 mice subjected to beta-secretase inhibitors, polythiophenes, or anti-A beta antibodies. Each treatment showed unique spatiotemporal A beta clearance, with polythiophenes emerging as a potent anti-A beta compound. Furthermore, aligning with a spatial-transcriptomic atlas revealed transcripts that correlate with the efficacy of each A beta therapy. As observed in this study, there is a striking dependence of specific treatments on the location and maturity of A beta plaques. This may also contribute to the clinical trial failures of A beta-therapies, suggesting that combinatorial regimens may be significantly more effective in clearing amyloid deposition., Funding Agencies|Swiss National Research Foundation [179040, 207872, 183563]; Gelu Foundation; Nomis Foundation; Swiss Personalized Health Network (SPHN) [2017DRI17]; USZ Foundation; Swedish Research Council [2016-00748]; European Research Council (BRAINCOMPATH) [670757]; NIH/NINDS [R01NS087159, R01NS091461]; NIH/NIA [RF1AG047666]; NIH/NIMH [RF1MH114227]