Biomarker-related phospho-tau217 appears in synapses around Aβ plaques prior to tau tangle in cerebral cortex of preclinical Alzheimer's disease.

Phospho-tau protein p-tau181 is a cerebrospinal fluid biomarker for Alzheimer's disease (AD), while p-tau217 is the most sensitive plasma biomarker for cerebral amyloid β (Aβ) load prior to tau pathology in preclinical AD. Diagnostic and prognostic use of these p-tau biomarkers requires neuropathological interpretation. Here, we analyzed the cellular localization of biomarker p-tau species in postmortem human brains harboring different extents of Aβ plaque and tau pathology.

Supplementation of essential amino acids suppresses age-associated sleep loss and sleep fragmentation but not loss of rhythm strength under yeast-restricted malnutrition in Drosophila.

Sleep quality and quantity decrease with age, and sleep disturbance increases the risk of many age-associated diseases. There is a significant relationship between nutritional status and sleep outcomes, with malnutrition inducing poor sleep quality in older adults. However, it remains elusive whether, and if so how, nutritional supplementation prevents age-associated sleep problems.

Alzheimer's Disease-Related Phospho-Tau181 Signals Are Localized to Demyelinated Axons of Parvalbumin-Positive GABAergic Interneurons in an App Knock-In Mouse Model of Amyloid-β Pathology.

Background: The tau protein phosphorylated at Thr181 (p-tau181) in cerebrospinal fluid and blood is a sensitive biomarker for Alzheimer's disease (AD). Increased p-tau181 levels correlate well with amyloid-β (Aβ) pathology and precede neurofibrillary tangle formation in the early stage of AD; however, the relationship between p-tau181 and Aβ-mediated pathology is less well understood. We recently reported that p-tau181 represents axonal abnormalities in mice with Aβ pathology (AppNLGF).

Role for μ-opioid receptor in antidepressant effects of δ-opioid receptor agonist KNT-127.

Previous pharmacological data have shown the possible existence of functional interactions between μ- (MOP), κ- (KOP), and δ-opioid receptors (DOP) in pain and mood disorders. We previously reported that MOP knockout (KO) mice exhibit a lower stress response compared with wildtype (WT) mice. Moreover, DOP agonists have been shown to exert antidepressant-like effects in numerous animal models.

is induced by aging and neurodegeneration to modulate stress signaling and its deficiency exacerbates tau-mediated neurodegeneration.

Toll-9 is most closely related to mammalian Toll-like receptors; however, physiological functions of Toll-9 remain elusive. We examined the roles of Toll-9 in fly brains in aging and neurodegeneration. mRNA levels were increased in aged fly heads accompanied by activation of nuclear factor-kappa B (NF-kB) and stress-activated protein kinase (SAPK) signaling, and many of these changes were modulated by in glial cells.

Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease.

Background: Knock-in (KI) mouse models of Alzheimer's disease (AD) that endogenously overproduce Aβ without non-physiological overexpression of amyloid precursor protein (APP) provide important insights into the pathogenic mechanisms of AD. Previously, we reported that App mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited emotional alterations before the onset of definitive cognitive deficits. To determine whether these mice exhibit deficits in learning and memory at more advanced ages, we compared the Morris water maze performance of App and App mice, which harbor only the Swedish mutation, with that of wild-type (WT) C57BL/6J mice at the age of 24 months.

Detection of circulating tumor cells in drainage venous blood from colorectal cancer patients using a new filtration and cytology-based automated platform.

Numerous technologies exist to detect circulating tumor cells (CTCs), although reports on cytological detection of CTCs remain limited. We recently developed a cytology-based CTC detection device using glass slides and light microscopy. In this study, we automated this previously manual device to improve its efficiency and cost effectiveness for clinical applications.

Repeated methamphetamine treatment increases spine density in the nucleus accumbens of serotonin transporter knockout mice.

Aim: Repeated psychostimulant drug treatment, including methamphetamine, in rodents readily produces behavioral sensitization, which reflects altered brain function caused by repeated drug exposure. Dendritic remodeling of medium spiny neurons in the nucleus accumbens is thought to be an essential mechanism underlying behavioral sensitization. We recently showed that chronic methamphetamine treatment did not produce behavioral sensitization in serotonin transporter knockout mice.

Cognitive and emotional alterations in App knock-in mouse models of Aβ amyloidosis.

Background: Alzheimer's disease (AD), the most common cause of dementia, is characterized by the progressive deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles. Mouse models of Aβ amyloidosis generated by knock-in (KI) of a humanized Aβ sequence provide distinct advantages over traditional transgenic models that rely on overexpression of amyloid precursor protein (APP). In App-KI mice, three familial AD-associated mutations were introduced into the endogenous mouse App locus to recapitulate Aβ pathology observed in AD: the Swedish (NL) mutation, which elevates total Aβ production; the Beyreuther/Iberian (F) mutation, which increases the Aβ42/Aβ40 ratio; and the Arctic (G) mutation, which promotes Aβ aggregation.

Integrated biology approach reveals molecular and pathological interactions among Alzheimer's Aβ42, Tau, TREM2, and TYROBP in Drosophila models.

Background: Cerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer's disease (AD), but interactions among these features remain poorly understood. Our previous multiscale molecular network models of AD revealed TYROBP as a key driver of an immune- and microglia-specific network that was robustly associated with AD pathophysiology. Recent genetic studies of AD further identified pathogenic mutations in both TREM2 and TYROBP.

Knockdown of wfs1, a fly homolog of Wolfram syndrome 1, in the nervous system increases susceptibility to age- and stress-induced neuronal dysfunction and degeneration in Drosophila.

Wolfram syndrome (WS), caused by loss-of-function mutations in the Wolfram syndrome 1 gene (WFS1), is characterized by juvenile-onset diabetes mellitus, bilateral optic atrophy, and a wide spectrum of neurological and psychiatric manifestations. WFS1 encodes an endoplasmic reticulum (ER)-resident transmembrane protein, and mutations in this gene lead to pancreatic β-cell death induced by high levels of ER stress. However, the mechanisms underlying neurodegeneration caused by WFS1 deficiency remain elusive.

EDEM Function in ERAD Protects against Chronic ER Proteinopathy and Age-Related Physiological Decline in Drosophila.

The unfolded protein response (UPR), which protects cells against accumulation of misfolded proteins in the ER, is induced in several age-associated degenerative diseases. However, sustained UPR activation has negative effects on cellular functions and may worsen disease symptoms. It remains unknown whether and how UPR components can be utilized to counteract chronic ER proteinopathies.

Sex differences in the effects of adolescent social deprivation on alcohol consumption in μ-opioid receptor knockout mice.

Rationale: Evidence based on clinical and experimental animal studies indicates that adolescent social deprivation influences alcohol consumption in a sex-dependent manner, perhaps by influencing stress responses. However, the mechanisms underlying the interaction between these phenomena remain to be elucidated. Since the μ-opioid receptor (MOP) has been reported to have key roles in social stress responses as well as the reinforcing/addictive effects of ethanol, MOP is a candidate molecule that may link adolescent social deprivation and subsequent alterations in alcohol consumption.

The Drosophila lingerer protein cooperates with Orb2 in long-term memory formation.

Recently mated Drosophila females were shown to be reluctant to copulate and to exhibit rejecting behavior when courted by a male. Males that experience mate refusal by a mated female subsequently attenuate their courtship effort toward not only mated females but also virgin females. This courtship suppression persists for more than a day, and thus represents long-term memory.

Developmental alterations in anxiety and cognitive behavior in serotonin transporter mutant mice.

Rationale: A promoter variant of the serotonin transporter (SERT) gene is known to affect emotional and cognitive regulation. In particular, the "short" allelic variant is implicated in the etiology of multiple neuropsychiatric disorders. Heterozygous (SERT(+/-)) and homozygous (SERT(-/-)) SERT mutant mice are valuable tools for understanding the mechanisms of altered SERT levels.

eNOS-dependent antisenscence effect of a calcium channel blocker in human endothelial cells.

Senescence of vascular endothelial cells is an important contributor to the pathogenesis of age-associated vascular disorders such as atherosclerosis. We investigated the effects of antihypertensive agents on high glucose-induced cellular senescence in human umbilical venous endothelial cells (HUVECs). Exposure of HUVECs to high glucose (22 mM) for 3 days increased senescence-associated- β-galactosidase (SA-β-gal) activity, a senescence marker, and decreased telomerase activity, a replicative senescence marker.

Impaired cliff avoidance reaction in dopamine transporter knockout mice.

Rationale: Impulsivity is a key feature of disorders that include attention-deficit/hyperactivity disorder (ADHD). The cliff avoidance reaction (CAR) assesses maladaptive impulsive rodent behavior. Dopamine transporter knockout (DAT-KO) mice display features of ADHD and are candidates in which to test other impulsive phenotypes.

Construction of a metagenomic library for the marine sponge Halichondria okadai.

Symbionts of the marine sponge Halichondria okadai are promising as a source of natural products. Metagenomic technology is a powerful tool for accessing the genetic and biochemical potential of bacteria. Hence, we established a method of recovering bacterial-enriched metagenomic DNA by stepwise centrifugation.