Biology subjects

Sasaguri, H.

Publications and source records attributed to Sasaguri, H..

3 recordsLinked to original sources

bioRxiv2020

α-Endosulfine regulates amyloid β42 via the modulation of neprilysin activity

The neuropeptide somatostatin (SST) regulates amyloid {beta} peptide (A{beta}) catabolism by enhancing neprilysin (NEP)-catalyzed proteolytic degradation. However, the mechanism by which SST regulates NEP activity remains unclear. Here we report the identification by differential proteomics of -endosulfine (ENSA), an endogenous ligand of the ATP-sensitive potassium (KATP) channel, as a negative regulator of NEP activity downstream of SST signaling. Genetic deficiency of ENSA resulted in enhanced NEP activity and decreased A{beta} deposition in the brains of wild-type and Alzheimers disease (AD) model mice. Pharmacological intervention to increase the probability of KATP channel opening reduced A{beta} deposition in AD model mice. Our findings provide new insights into possible mechanisms to prevent AD.

neuroscience↗

bioRxiv2020

A non-human primate model of familial Alzheimer's disease

Alzheimers disease (AD) is a major cause of dementia, with the number of patients with this condition anticipated to exceed 50 million worldwide in the near future. Despite extensive research efforts, no effective measures are available to facilitate the prevention or treatment of AD, which is due in part to a lack of animal models able to closely replicate a human-like disease state. Here, we describe the generation of three mutant marmoset individuals in which exon 9 of PSEN1 gene product has been deleted (PSEN1-{Delta}E9). Such {Delta}E9 mutations have been reported to cause early on-set familial AD (references1-5). We used Transcription Activator-Like Effector Nuclease (TALEN) to destroy the 3 splice site of exon 9 in the marmoset PSEN1 gene. To this end, TALEN exhibits high genome-editing efficacy, generates few off-target effects, and produces minimal mosaicism. Indeed, whole genome sequencing and other analyses illustrated an absence of off-target effects and an apparent absence of mosaicism. Fibroblasts obtained from newborn marmosets exhibited uncleaved full-length presenilin 1 protein (PS1) caused by the perturbation of PS1 endoproteolysis as well as an increased ratio of A{beta}42/A{beta}40 production, a signature of familial AD pathogenesis. To our knowledge, this is the first non-human primate model of familial AD. We intend to make our marmoset model available to the research community to facilitate the global fight against AD.

neuroscience↗

bioRxiv2020

Somatostatin receptor subtypes 1 and 4 redundantly regulate neprilysin, the major amyloid beta-degrading enzyme, in brain

Alzheimers disease (AD) brains are characterized by increased levels of the pathogenic amyloid beta (A{beta}) peptide, which accumulates into extracellular plaques. Finding a way to lower A{beta} levels is fundamental for the prevention and treatment of AD. Neprilysin is the major A{beta} degrading enzyme which is regulated by the neuropeptide somatostatin. Here we used a combination of in vitro and in vivo approaches to identify the subtype specificity of the five somatostatin receptors (SSTs) expressed in the brain, involved in the regulation of neprilysin. Using a battery of Sst double knockout (dKO) mice we show that neprilysin is regulated by SST1 and SST4 in a redundant manner. Sst1 and Sst4 dKO mice exhibit a specific decrease of presynaptic neprilysin in the Lacunosum molecular layer. Moreover, a genetic deficiency of Sst1 and Sst4 in amyloid beta precursor protein (App) knock-in mice, an AD mouse model, aggravates the A{beta} pathology in the hippocampus. As a first proof of concept towards an A{beta}-lowering strategy involving neprilysin, we demonstrate that treatment with an agonist selective for SST1 and SST4 ameliorates the A{beta} pathology and improves cognition in the App knock-in AD mouse model.

neuroscience↗