Biology subjects

Takamura, R.

Publications and source records attributed to Takamura, R..

3 recordsLinked to original sources

bioRxiv2023

Fluctuation of lysosomal protein degradation in neural stem cells of postnatal mouse brain

Lysosomes are intracellular organelles responsible for degrading diverse macromolecules delivered from several pathways, such as the endo-lysosomal and autophagic pathways. Recent reports have suggested that lysosomes are essential in regulating neural stem cells in developing, adult, and aged brains. However, the activity of these lysosomes has not yet been monitored in these brain tissues. Here, we report a new probe to measure lysosomal protein degradation in brain tissue by immunostaining. Our results demonstrate the fluctuation of lysosomal protein degradation in neural stem cells depending on age and brain disorder. Neural stem cells increase lysosomal activity during hippocampal development in the dentate gyrus, but aging and aging-related disease reduces their activity. In addition, physical exercise increases lysosomal activity in neural stem cells and astrocytes. We hypothesize three different stages of lysosomal activity: the increase in development, the stable state for the adult stage, and the reduction by damages with age or disease.

neuroscience↗

bioRxiv2021

Neprilysin-sensitive amyloidogenic Aβ versus IDE-sensitive soluble Aβ: a probable mechanistic cause for sporadic Alzheimer's disease

Neprilysin (NEP) and insulin-degrading enzyme (IDE) are considered the two major catabolic enzymes that degrade amyloid {beta} peptide (A{beta}), the primary cause of Alzheimers disease (AD). However, their roles in A{beta} metabolism in vivo have never been compared in an impartial and side-by-side manner. Here, we crossbred single App knock-in mice with NEP (Mme) KO mice and with IDE (Ide) KO mice to generate double mutants that were analyzed for their biochemical and A{beta} pathology properties. We found that NEP is responsible for the metabolism of amyloidogenic insoluble A{beta} whereas IDE affects soluble A{beta}. A deficiency of NEP, but not of IDE, augmented the formation of A{beta} plaques, dystrophic neurites, and astrocytic and microglial activation, all of which are key pathological events in the development of AD. In addition, a deficiency of NEP had no significant impact on the levels of various neuropeptides (somatostatin, substance P, cholecystokinin, and neuropeptide Y), well known to be in vitro substrates for NEP, presumably because NEP is expressed in secretory vesicles and on the presynaptic membranes of excitatory neurons while most if not all neuropeptides are secreted from inhibitory neurons. This argues against the concern that NEP up-regulation for treatment of preclinical AD would reduce the levels of these neuropeptides. These findings indicate that NEP relatively selectively degrades A{beta} in the brain. Whereas familial AD (FAD) is unambiguously caused by an increased anabolism of A{beta}, and of A{beta} 42 and A{beta} 43 in particular, the anabolism of A{beta} appears unaffected before its deposition in the brain that subsequently leads to the onset of sporadic AD (SAD). These observations thus suggest that NEP-sensitive amyloidogenic A{beta} likely plays a primary pathogenic role in the etiology of SAD. Our findings are consistent with the aging-dependent decline of NEP expression in human brain and with recent genome-wide association studies (GWAS) indicating that variants of the gene encoding NEP (MME) are associated with the risk of SAD development. Taken together, our results imply that the aging-associated decrease in NEP expression is a primary cause of SAD and could thus be a target for the treatment of preclinical AD once other factors such as apolipoprotein E genotypes have also been considered.

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↗