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.

Mosaic variants of neurodevelopmental and mitochondrial genes in postmortem paraventricular thalamus in bipolar disorder detected by deep exome sequencing.

Aim: The genetic architecture of bipolar disorder (BD) remains incompletely understood despite extensive genomic studies. Postzygotic mosaic variants have emerged as promising contributors to BD; however, the landscape of such variants in the BD brain has yet to be elucidated.

Methods: We analyzed mosaic variants in the paraventricular thalamic region (PVR) from 18 Japanese BD cases and 11 controls using deep whole-exome sequencing.

Association of rare missense variants with Alzheimer's disease in the Japanese population.

BackgroundLittle is known about the rare missense variants (RMVs) of in East Asians, including the Japanese, and their association with Alzheimer's disease (AD) and lipid metabolism.ObjectiveTo identify RMVs in the Japanese population and investigate their association with AD and lipid metabolism, including low-density lipoprotein cholesterol levels.Methods RMVs were explored in the Niigata (NIG; 2589 subjects) and Tohoku (ToMMo; 3307 subjects) cohorts.

Bridging minds: Participant perspectives on postmortem brain research and engagement.

Postmortem research participation remains underrepresented in research ethics discussions. Herein, we examined the associated perspectives of individuals preregistered with the Brain Bank for Aging Research at the Tokyo Metropolitan Institute of Gerontology. We conducted a postal survey targeting 88 preregistrants, yielding 52 responses (response rate: 59.

Syk inhibitors reduce tau protein phosphorylation and oligomerization.

Spleen tyrosine kinase (Syk), a non-receptor-type tyrosine kinase, has a wide range of physiological functions. A possible role of Syk in Alzheimer's disease (AD) has been proposed. We evaluated the localization of Syk in the brains of patients with AD and control participants.

A pentavalent peptide vaccine elicits Aβ and tau antibodies with prophylactic activity in an Alzheimer's disease mouse model.

Amyloid-β (Aβ) and hyperphosphorylated tau protein are targets for Alzheimer's Disease (AD) immunotherapies, which are generally focused on single epitopes within Aβ or tau. However, due to the complexity of both Aβ and tau in AD pathogenesis, a multipronged approach simultaneously targeting multiple epitopes of both proteins could overcome limitations of monotherapies. Herein, we propose an active AD immunotherapy based on a nanoparticle vaccine comprising two Aβ peptides (1-14 and pyroglutamate pE3-14) and three tau peptides (centered on phosphorylated pT181, pT217 and pS396/404).

Integrated Spatial Multi-Omics Study of Postmortem Brains of Alzheimer's Disease.

Pathological hallmark of Alzheimer's disease (AD) is characterized by the accumulation and aggregation of amyloid β (Aβ) peptides into extracellular plaques of the brain. Clarification of the process of how soluble Aβ starts to assemble into amyloid fibrils is an essential step in elucidating the pathogenesis of AD. In our previous study, Aβ proteoforms including full-length Aβ40 and Aβ42/43 with N- and C-terminal truncated forms were visualized in postmortem brains from AD patients with matrix-assisted laser desorption/ionization-based mass spectrometry imaging (MALDI-MSI).

Proteomic profile of nuclei containing p62-positive inclusions in a patient with neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the neurons, glial cells, and other somatic cells. Although CGG repeat expansions in NOTCH2NLC have been identified in most East Asian patients with NIID, the pathophysiology of NIID remains unclear. Ubiquitin- and p62-positive intranuclear inclusions are the pathological hallmark of NIID.

ELISA Evaluation of Tau Accumulation in the Brains of Patients with Alzheimer Disease.

Despite the routine use of sandwich enzyme-linked immunosorbent assays (ELISAs) for quantifying tau levels in CSF and plasma, tau accumulations in the brains of patients with Alzheimer disease (AD) have rarely been evaluated by this method. Thus, by introducing several tau ELISAs that target different epitopes, we evaluated accumulated tau levels in postmortem brains depending on disease stage, brain areas, and other AD-related changes. Notably, tau levels in insoluble fraction determined by each ELISAs differ depending on the epitopes of antibodies: non-AD control samples yield relatively high signals when an antibody against the N-terminal region of tau is used.

Neuron-specific analysis of histone modifications with post-mortem brains.

Histone modifications govern chromatin structures and regulate gene expression to orchestrate cellular functions in the central nervous system, where neuronal cells are postmitotic and developmentally inactive, the functional and age-dependent changes also accumulate in the epigenetic states. Because the brain is composed of several types of cells, such as the neurons, glial cells, and vascular cells, the analysis of histone modifications using bulk brain tissue might obscure alterations specific to neuronal cells. Furthermore, among the various epigenetic traits, analysis of the genome-wide distribution of DNA methylation in the bulk brain is predominantly a reflection of DNA methylation of the non-neuronal cells, which may be a potential caveat of previous studies on neurodegenerative diseases using bulk brains.