Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration

Abstract

The brains of Alzheimer’s disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer’s disease (AD) is subject to debate as the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of A. We use Drosophila, C. elegans and D. rerio to show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.

Steering Molecular Activity with Optogenetics: Recent Advances and Perspectives

“…A) A scattered plot depicting selected work of optogenetic control of molecular activities in the past three years. Strategies are grouped into three categories: cell signaling (yellow), [ 20,34,38–49,51a,52–59,61,67,69–76,79–83,66 ] organelle manipulation (cyan), [ 84–87,89–100 ] and genetic regulation (magenta). [ 101,102,105–107,109–118 ] Excitation wavelength refers to the light used to activate the optogenetic proteins, which are individually labeled.…”

“…Although cytotoxicity of Amyloid‐β was confirmed in both soluble and light‐induced solid phases, metabolic damage occurs only in the solid phase upon light stimulation. [ 100 ]…”

Advanced Optogenetic-Based Biosensing and Related Biomaterials

“…Kaur. et al [ 118 ] demonstrated the use of optogenetic Amyloidβ to monitor in vivo protein aggregation while fluorescent optogenetic Amyloid-beta was shown to enable discrimination between metabolic and physical damages in neurodegeneration [ 119 ] as well in vivo settings. Development of cell-free systems, as part of the synthetic biology field, to become a critical platform in biological studies [ 120 ].…”

Total Recall: Lateral Habenula and Psychedelics in the Study of Depression and Comorbid Brain Disorders

“…The use of animal models to dissect the underpinnings of human brain disorders is irreplaceable [76], yet studies have to fulfill a tall order of requirements where differences in cellular physiology, species differences, and the differences due to the complexity of the circuitry need to be taken into account while generating meaningful, transferable knowledge. The studies on MOR and NMDAR described above both used cLH rodents [13,64].…”