The β- and γ-secretase-driven cleavage of the amyloid precursor protein (APP) gives rise to the amyloid β peptide, which is believed to be the main driver of neurodegeneration in Alzheimer’s disease (AD). As it is prominently detectable in extracellular plaques in post-mortem AD brain samples, research in recent decades focused on the pathological role of extracellular amyloid β aggregation, widely neglecting the potential meaning of very early generation of amyloid β inside the cell. In the last few years, the importance of intracellular amyloid β (iAβ) as a strong player in neurodegeneration has been indicated by a rising number of studies. In this review, iAβ is highlighted as a crucial APP cleavage fragment, able to manipulate intracellular pathways and foster neurodegeneration. We demonstrate its relevance as a pathological marker and shed light on initial studies aiming to modulate iAβ through pharmacological treatment, which has been shown to have beneficial effects on cognitive properties in animal models. Finally, we display the relevance of viral infections on iAβ generation and point out future directions urgently needed to manifest the potential relevance of iAβ in Alzheimer’s disease.

We report the design, synthesis, and biological char-acterization of a pseudo-NP (PNP) collection in-spired by the mesembrine alkaloid scaffold. A scala-ble, microwave-assisted intramolecular Diels-Alder furan cyclization enabled efficient access to the 3a-aryloctahydroindole (AOHI) core, which served as a versatile intermediate for diversification through NP-fragment fusion. The resulting AOHI-based PNPs explore chemical space bridging properties of NPs and drug-like molecules. Morphological and bioen-ergetic profiling revealed distinct mitochondrial phe-notypes, including altered morphological features and respiration consistent with complex I perturba-tion. Seahorse flux analysis showed that fusion with a pyridine robustly modulated mitochondrial function, indicating an upstream effect of complex V. Taken together, these findings highlight the AOHI scaffold as a versatile and synthetically accessible alkaloid-derived fragment for pseudo-natural product design and as a valuable source for novel biologically active compound classes.