Optical resolution photoacoustic imaging of uneven samples without z-scanning is transformative for the fast analysis and diagnosis of diseases. However, current approaches to elongate the depth of field (DOF) typically imply cumbersome postprocessing procedures, bulky optical element ensembles, or substantial excitation beam side lobes. Metasurface technology allows for the phase modulation of light and the miniaturization of imaging systems to wavelength-size thickness. Here, we propose a metalens composed of submicrometer-thick titanium oxide nanopillars, which generates an elongated beam of diffraction-limited diameter with an aspect ratio of 286 and a uniform intensity throughout the DOF. The metalens enhances visualization of phantom samples with tilted surfaces compared to conventional lenses. Moreover, the volumetric imaging of neuromelanin is facilitated for depths of up to 500 micrometers within the human midbrain and forebrain organoids that are 3D biological models of human brain regions. This approach provides a miniaturized platform for neurodegenerative disease diagnosis and drug discovery.

Recent multi‐omics analyses paved the way for a comprehensive understanding of pathological processes. However, only few studies have explored Alzheimer’s disease (AD) despite the possibility of biological subtypes within these patients. For this study, unsupervised classification of four datasets (genetics, miRNA transcriptomics, proteomics, and blood‐based biomarkers) using Multi‐Omics Factor Analysis+ (MOFA+), along with systems‐biological approaches following various downstream analyses are performed. New subgroups within 170 patients with cerebral amyloid pathology (Aβ+) are revealed and the features of them are identified based on the top‐rated targets constructing multi‐omics factors of both whole (M‐TPAD) and immune‐focused models (M‐IPAD). The authors explored the characteristics of subtypes and possible key‐drivers for AD pathogenesis. Further in‐depth studies showed that these subtypes are associated with longitudinal brain changes and autophagy pathways are main contributors. The significance of autophagy or clustering tendency is validated in peripheral blood mononuclear cells (PBMCs; n = 120 including 30 Aβ‐ and 90 Aβ+), induced pluripotent stem cell‐derived human brain organoids/microglia (n = 12 including 5 Aβ‐, 5 Aβ+, and CRISPR‐Cas9 apolipoprotein isogenic lines), and human brain transcriptome (n = 78). Collectively, this study provides a strategy for precision medicine therapy and drug development for AD using integrative multi‐omics analysis and network modelling.

Rian Kang, Soomin Park, Saewoon Shin, Gyusoo Bak & Jong-Chan Park. BMB Reports 2024;57:311-7. https://doi.org/10.5483/BMBRep.2024-0077

Taehwan Kwak, Si-Hyung Park, Siyoung Lee, Yujeong Shin, Ki-Jun Yoon, Seung-Woo Cho, Jong-Chan Park, Seung-Ho Yang, Heeyeong Cho, Heh-In Im, Sun-Ju Ahn, Woong Sun, Ji Hun Yang. IJSC -0001;0:. https://doi.org/10.15283/ijsc24056

Noninvasive monitoring of Alzheimer's disease (AD) biomarkers is essential for early diagnosis and treatment efficacy. However, noninvasive monitoring of tau protein secretion, a key biomarker of AD, across developmental stages, age‐related variations, and the interaction between apolipoprotein E (APOE) and the tau protein axis is not yet accomplished. Here, the label‐free and non‐invasive detection of multiple tau variants dynamics across developmental stages, age‐related variants, and various APOE isogenic genotyes is presented to investigate the APOE–tau axis using human cerebral organoids (hCOs) combined with surface‐enhanced Raman spectroscopy (SERS). Principal component analysis (PCA) of SERS signals successfully identifies four developmental stages of hCOs: embryonic body, neuronal differentiation, maturation, and maintenance phases. Temporal dynamics of age‐related tau protein secretion are observed, reflecting characteristics associated with AD, which are diminished by astrocyte expression. PCA‐based dimensionality reduction of SERS signals further reveals distinct clustering for different APOE isogenic genotypes, with tau protein secretion increasing from APOE2/E2 to APOE4/E4, providing direct insight into the APOE–tau axis in AD. This study introduces a novel method for the non‐invasive clinical assessments of disease conditions, dynamics, and the relationship between APOE and tau in AD.

Alzheimer's disease (AD) is characterized by significant alterations in hippocampal function and structure, but the molecular mechanisms underlying the hippocampal region remain elusive. We integrated multiple transcriptome datasets including human or rat hippocampus (GSE173955, GSE129051, GSE84422) to identify candidate genes. Subsequent analyses including gene ontology analysis and protein–protein interaction mapping were performed to identify key genes and pathways. We found that glutamate ionotropic receptor NMDA‐type subunit 3A (GRIN3A) and glutamate metabotropic receptor 8 (GRM8), which are related to the glutamatergic system, were the top two annotated genes and directly related to MAPT, which encodes a tau protein. Since there is no direct evidence of interaction between tauopathy and these genes in AD, further transcriptomic data (GSE125957, GSE56772) from tau transgenic mice and experimental validations through primary rat hippocampal neurons and induced pluripotent stem cell (iPSC)‐derived brain organoids were performed. Interestingly, we identified that decreased NR3A (encoded by GRIN3A) and mGluR8 (encoded by GRM8) are correlated with tauopathy and loss of postsynaptic function in AD. Taken together, our results identified a novel tauopathy biomarker GRIN3A in AD. Furthermore, our findings suggest that an integrated approach combining public databases and diverse experimental validations can contribute to the advancement of precision medicine therapies.