Eye-Tracking-Based Cognitive Assessment Efficiently Detects Mild Cognitive Decline in the Predementia Stage.

Introduction: The early detection of cognitive decline is key to maximizing the benefits of preventive and therapeutic interventions against dementia. Generally, dementia is first assessed by interview-based neuropsychological tests, but the lengthy interview and mental stress during the assessment process make screenings inefficient. We previously developed a rapid screening test for dementia using an eye-tracking technology (eye-tracking-based cognitive assessment [ETCA]) and reported its utility for clinically detecting cognitive impairment in dementia cases.

Imaging Biomarker for Early-Stage Alzheimer Disease: Utility of Hippocampal Histogram Analysis of Diffusion Metrics.

Background And Purpose: Biomarkers have been required for diagnosing early Alzheimer disease. We assessed the utility of hippocampal diffusion parameters for diagnosing Alzheimer disease pathology in mild cognitive impairment.

Materials And Methods: Sixty-nine patients with mild cognitive impairment underwent both CSF measurement and multi-shell diffusion imaging at 3T.

RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS.

Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone-collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear.

Antiepileptic Drugs Modulate Alzheimer-Related Tau Aggregation in a Neuronal Activity-Independent Manner.

Introduction: A rapidly increasing number of patients with dementia present a serious social problem. Recently, the incidence of epilepsy in patients with Alzheimer's disease (AD) is increasing, drawing attention to the pathological relationship between the two conditions. Clinical studies have suggested the protective action of antiepileptic agents on dementia; however, the underlying mechanism remains unknown.

Novel pathophysiological roles of α-synuclein in age-related vascular endothelial dysfunction.

Although α-synuclein (SNCA) is a well-known pathological molecule involved in synucleinopathy in neurons, its physiological roles remain largely unknown. We reported that serum SNCA levels have a close inverse correlation with blood pressure and age, which indicates the involvement of SNCA in age-related endothelial dysfunction. Therefore, this study aimed to elucidate the molecular functions of SNCA in the endothelium.

A novel chronic dural port platform for continuous collection of cerebrospinal fluid and intrathecal drug delivery in free-moving mice.

Background: Cerebrospinal fluid (CSF) provides a close representation of pathophysiological changes occurring in the central nervous system (CNS); therefore, it has been employed in pathogenesis research and biomarker development for CNS disorders. CSF obtained from valid mouse models relevant to CNS disorders can be an important resource for successful biomarker and drug development. However, the limited volume of CSF that can be collected from tiny intrathecal spaces and the technical difficulties involved in CSF sampling has been a bottleneck that has hindered the detailed analysis of CSF in mouse models.

Peripheral Aβ acts as a negative modulator of insulin secretion.

Type 2 diabetes mellitus is known to be a risk factor for Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. In AD, the cerebral accumulation of amyloid β (Aβ) triggers a pathological cascade leading to neurodegeneration. Plasma Aβ levels are thought to reflect the brain amyloid pathology and currently used as a diagnostic biomarker of AD.

Upregulated expression of a subset of genes in ;/ mice: Evidence of an interaction between diabetes-linked obesity and Alzheimer's disease.

Clinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. However, the mechanism by which obesity/diabetes and AD interact with each other and contribute to dementia remains elusive. To obtain insights into their interaction at molecular levels, we performed gene expression analysis of ;/ mice, which were generated by crossing transgenic AD model mice (APP23 mice) with / mice, which are obese and mildly diabetic.

Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3β) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation.

It has been suggested that aberrant activation of glycogen synthase kinase-3-beta (GSK-3β) can trigger abnormal tau hyperphosphorylation and aggregation, which ultimately leads to neuronal/synaptic damage and impaired cognition in Alzheimer disease (AD). We examined if isoform-selective partial reduction of GSK-3β can decrease pathological tau changes, including hyperphosphorylation, aggregation, and spreading, in mice with localized human wild-type tau (hTau) expression in the brain. We used adeno-associated viruses (AAVs) to express hTau locally in the entorhinal cortex of wild-type and GSK-3β hemi-knockout (GSK-3β-HK) mice.

Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer's Disease.

To elucidate the role of Tau isoforms and post-translational modification (PTM) stoichiometry in Alzheimer's disease (AD), we generated a high-resolution quantitative proteomics map of 95 PTMs on multiple isoforms of Tau isolated from postmortem human tissue from 49 AD and 42 control subjects. Although Tau PTM maps reveal heterogeneity across subjects, a subset of PTMs display high occupancy and frequency for AD, suggesting importance in disease. Unsupervised analyses indicate that PTMs occur in an ordered manner, leading to Tau aggregation.

Tau Propagation as a Diagnostic and Therapeutic Target for Dementia: Potentials and Unanswered Questions.

A unique clinical course of Alzheimer's disease (AD), beginning with memory deficit as the earliest symptom, is well-correlated with a progressive pattern of intracellular aggregates of tau (neurofibrillary tangles), which spread from the medial temporal lobe to other brain areas in a stereotypical manner. Recent findings from basic research using and models demonstrated that pathological forms of extracellular tau can be taken up by cells and induce intracellular tau aggregates. On the basis of these neuropathological observations and experimental findings, the "tau propagation hypothesis" has been proposed, in which the stereotypical spreading of the tau pathology observed in the brain of AD patients can be explained by the interneuron transfer of the pathological form of tau.

Novel properties of myoferlin in glucose metabolism via pathways involving modulation of adipose functions.

While adipose tissue is required to maintain glucose metabolism, excessive calorie intake induces obesity via mechanisms including accelerated proliferation and differentiation of preadipocytes, leading to insulin resistance. Here, we investigated the role of myoferlin (MYOF), a ferlin family protein, in regulating glucose metabolism by mainly focusing on its unknown role in adipose tissue. Whereas young MYOF knockout (KO) mice on a normal diet showed aggravated glucose tolerance and insulin sensitivity, those on a high-fat diet (HFD) showed preserved glucose tolerance with an attenuated gain of body weight, reduced visceral fat deposits, and less severe fatty liver.

Increased levels of Aβ42 decrease the lifespan of ob/ob mice with dysregulation of microglia and astrocytes.

Clinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. Although the mechanisms underlying these associations remain elusive, the bidirectional interactions between obesity/diabetes and Alzheimer's disease (AD) may be involved in them. Both obesity/diabetes and AD significantly reduce life expectancy.

Roles of vascular risk factors in the pathogenesis of dementia.

The number of people with dementia is rapidly growing along with the aging of society and is becoming a social issue worldwide. The results of recent clinical and basic studies have suggested that vascular risk factors, such as hypertension and diabetes mellitus, affect the pathogenesis of dementia. Cerebrovascular damage due to vascular risk factors directly triggers vascular dementia, and it is becoming more apparent that vascular risk factors also increase the risk of neurodegenerative Alzheimer's disease, which is associated with the accumulation of neurotoxic proteins in the brain.

Novel Method for Rapid Assessment of Cognitive Impairment Using High-Performance Eye-Tracking Technology.

A rapid increase in the number of patients with dementia has emerged as a global health challenge. Accumulating evidence suggests that early diagnosis and timely intervention can delay cognitive decline. The diagnosis of dementia is commonly performed using neuropsychological tests, such as the Mini-Mental State Examination (MMSE), administered by trained examiners.

Effect of heat stress on blood-brain barrier integrity in iPS cell-derived microvascular endothelial cell models.

The incidence of heatstroke has been increasing. Heatstroke has been shown to affect physiological barrier functions. However, there are few studies of the effect of heat stress on the blood-brain barrier (BBB) function.

Frequency-dependent exacerbation of Alzheimer's disease neuropathophysiology.

Neuronal activity patterns are disrupted in neurodegenerative disorders, including Alzheimer's disease (AD). One example is disruption of corticothalamic slow oscillations responsible for sleep-dependent memory consolidation. Slow waves are periodic oscillations in neuronal activity occurring at frequencies of <1 Hz.

Therapeutic Vaccine Against S100A9 (S100 Calcium-Binding Protein A9) Inhibits Thrombosis Without Increasing the Risk of Bleeding in Ischemic Stroke in Mice.

Decreased adherence to daily ingestion of antiplatelet drugs is a critical issue, increasing mortality and morbidity in poststroke patients. As vaccination could be a promising approach to solving this, we designed an antiplatelet vaccine that inhibited S100A9 (S100 calcium-binding protein A9)/CD36 (cluster of differentiation 36) signaling in platelets, which was reported to be a key signal in arterial thrombosis, but not hemostasis. Immunization with this vaccine induced a sustainable increase in the anti-S100A9 antibody titer for >2 months and an additional booster immunization enhanced the antibody production further.

Secretion and Uptake of α-Synuclein Via Extracellular Vesicles in Cultured Cells.

In Parkinson's disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular α-synuclein (α-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of α-syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether altered molecular properties of α-syn can influence the distribution and secretion of α-syn in human neuroblastoma cells.

Angiotensin-converting enzyme 2 deficiency accelerates and angiotensin 1-7 restores age-related muscle weakness in mice.

Background: A pharmacologic strategy for age-related muscle weakness is desired to improve mortality and disability in the elderly. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II into angiotensin 1-7, a peptide known to protect against acute and chronic skeletal muscle injury in rodents. Since physiological aging induces muscle weakness via mechanisms distinct from other muscle disorders, the role of ACE2-angiotensin 1-7 in age-related muscle weakness remains undetermined.

Progression of Alzheimer's disease, tau propagation, and its modifiable risk factors.

The number of patients with Alzheimer's disease (AD) has been increasing exponentially side by side with aging societies worldwide. Symptoms of AD worsen over time due to progressive neurodegeneration, requiring institutional care at the later stage and resulting in a heavy burden on patients, caregivers, and the public-health system. AD neuropathology is characterized by cerebral accumulation and aggregation of amyloid-β (Aβ) and tau proteins.

CRISPR/Cas9 Mediated Disruption of the Swedish APP Allele as a Therapeutic Approach for Early-Onset Alzheimer's Disease.

The APPswe (Swedish) mutation in the amyloid precursor protein (APP) gene causes dominantly inherited Alzheimer's disease (AD) as a result of increased β-secretase cleavage of the amyloid-β (Aβ) precursor protein. This leads to abnormally high Aβ levels, not only in brain but also in peripheral tissues of mutation carriers. Here, we selectively disrupted the human mutant APP allele using CRISPR.

Mutant torsinA in the heterozygous DYT1 state compromises HSV propagation in infected neurons and fibroblasts.

Most cases of early onset torsion dystonia (DYT1) are caused by a 3-base pair deletion in one allele of the TOR1A gene causing loss of a glutamate in torsinA, a luminal protein in the nuclear envelope. This dominantly inherited neurologic disease has reduced penetrance and no other medical manifestations. It has been challenging to understand the neuronal abnormalities as cells and mouse models which are heterozygous (Het) for the mutant allele are quite similar to wild-type (WT) controls.

Characterization of TauC3 antibody and demonstration of its potential to block tau propagation.

The spread of neurofibrillary tangle (NFT) pathology through the human brain is a hallmark of Alzheimer's disease (AD), which is thought to be caused by the propagation of "seeding" competent soluble misfolded tau. "TauC3", a C-terminally truncated form of tau that is generated by caspase-3 cleavage at D421, has previously been observed in NFTs and has been implicated in tau toxicity. Here we show that TauC3 is found in the seeding competent high molecular weight (HMW) protein fraction of human AD brain.