Affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA
Keywords: a. neural degeneration; i. lifespan
Alzheimer’s disease (AD) is a neurodegenerative disease associated with nearly 6 million deaths in the U.S. every year. AD is characterized by a loss of memory, decline in cognitive abilities, and changes in mood and personality. A hallmark of AD pathology is the presence of Aβ plaques, which are formed by the aggregation of Aβ peptides. The Aβ1-42 peptide is produced by the cleavage of amyloid precursor protein (APP), first by β-secretase and then ɣ-secretase. An alternative pathway uses α-secretase instead of β-secretase and generates a peptide called P3 (Aβ17-42), that is 16 amino acids shorter than Aβ1-42 and is composed of the hydrophobic portion of Aβ1-42. This P3 cleavage pathway is often characterized as non-amyloidogenic, however, recent evidence suggests P3 is amyloidogenic (Kuhn, et al., 2020). As such, there is reason to think that P3 could have similar deleterious effects as Aβ1-42. The purpose of our research is to characterize P3 peptide’s neurotoxicity and determine whether it interacts with Aβ. To investigate this, we generated P3 expressing flies, Aβ1-42 expressing flies, and Aβ1-42/P3 co-expressing flies, in which the peptides were expressed pan-neuronally, to examine the neurodegenerative effects of these two peptides independently, as well as their synergistic neurotoxic effects. RT-PCR experiments have confirmed expression of the transgenes. A longevity assay was conducted to measure lifespan in the transgenic flies and the Rapid Iterative Negative Geotaxis (RING) assay was performed to monitor their locomotor performance in relation to age. These results, along with electron micrograph analysis of the peptides’ effects when expressed in fly eyes, indicate that P3 expression alone has similar, but less severe, effects as Aβ on lifespan, behavior, and neurodegeneration. Our results also suggest that P3 exacerbates the effects of Aβ1-42 when co-expressed. RNA sequencing is being used to further investigate the effects of these peptides by examining whether the expression of neurodegenerative-related genes and neuroplasticity-related genes, known to be affected by Aβ1-42, are similarly affected by P3. We will also conduct co-immunoprecipitation experiments using Aβ1-42/P3 co-expressing flies to determine whether the two peptides directly interact. Our research will help to determine whether P3 might be a direct contributing factor to AD pathology and/or have an effect via its interaction with Aβ.