Whole-brain functional connectivity predicts groupwise and sex-specific tau PET in preclincal Alzheimer's disease.

Preclinical Alzheimer's disease, characterized by the initial accumulation of amyloid and tau pathologies without symptoms, presents a critical opportunity for early intervention. Yet, the interplay between these pathological markers and the functional connectome during this window remains understudied. We therefore set out to elucidate the relationship between the functional connectome and amyloid and tau, as assessed by PET imaging, in individuals with preclinical AD using connectome-based predictive modeling (CPM). We found that functional connectivity predicts tau PET, outperforming amyloid PET models. These models were predominantly governed by linear relationships between functional connectivity and tau. Tau models demonstrated a stronger correlation to global connectivity than underlying tau PET. Furthermore, we identify sex-based differences in the ability to predict regional tau, without any underlying differences in tau PET or global connectivity. Taken together, these results suggest tau is more closely coupled to functional connectivity than amyloid in preclinical disease, and that multimodal predictive modeling approaches stand to identify unique relationships that any one modality may be insufficient to discern.

Piezo1 regulates cholesterol biosynthesis to influence neural stem cell fate during brain development.

Mechanical forces and tissue mechanics influence the morphology of the developing brain, but the underlying molecular mechanisms have been elusive. Here, we examine the role of mechanotransduction in brain development by focusing on Piezo1, a mechanically activated ion channel. We find that Piezo1 deletion results in a thinner neuroepithelial layer, disrupts pseudostratification, and reduces neurogenesis in E10.5 mouse embryos. Proliferation and differentiation of Piezo1 knockout (KO) mouse neural stem cells (NSCs) isolated from E10.5 embryos are reduced in vitro compared to littermate WT NSCs. Transcriptome analysis of E10.5 Piezo1 KO brains reveals downregulation of the cholesterol biosynthesis superpathway, in which 16 genes, including Hmgcr, the gene encoding the rate-limiting enzyme of the cholesterol biosynthesis pathway, are downregulated by 1.5-fold or more. Consistent with this finding, membrane lipid composition is altered, and the cholesterol levels are reduced in Piezo1 KO NSCs. Cholesterol supplementation of Piezo1 KO NSCs partially rescues the phenotype in vitro. These findings demonstrate a role for Piezo1 in the neurodevelopmental process that modulates the quantity, quality, and organization of cells by influencing cellular cholesterol metabolism. Our study establishes a direct link in NSCs between PIEZO1, intracellular cholesterol levels, and neural development.

Spatiotemporal dynamics of PIEZO1 localization controls keratinocyte migration during wound healing.

Keratinocytes, the predominant cell type of the epidermis, migrate to reinstate the epithelial barrier during wound healing. Mechanical cues are known to regulate keratinocyte re-epithelialization and wound healing; however, the underlying molecular transducers and biophysical mechanisms remain elusive. Here, we show through molecular, cellular, and organismal studies that the mechanically activated ion channel PIEZO1 regulates keratinocyte migration and wound healing. Epidermal-specific Piezo1 knockout mice exhibited faster wound closure while gain-of-function mice displayed slower wound closure compared to littermate controls. By imaging the spatiotemporal localization dynamics of endogenous PIEZO1 channels, we find that channel enrichment at some regions of the wound edge induces a localized cellular retraction that slows keratinocyte collective migration. In migrating single keratinocytes, PIEZO1 is enriched at the rear of the cell, where maximal retraction occurs, and we find that chemical activation of PIEZO1 enhances retraction during single as well as collective migration. Our findings uncover novel molecular mechanisms underlying single and collective keratinocyte migration that may suggest a potential pharmacological target for wound treatment. More broadly, we show that nanoscale spatiotemporal dynamics of Piezo1 channels can control tissue-scale events, a finding with implications beyond wound healing to processes as diverse as development, homeostasis, disease, and repair.

The skin is the largest organ of the body. It enables touch sensation and protects against external insults. Wounding of the skin exposes the body to an increased risk of infection, disease and scar formation. During wound healing, the cells in the topmost layer of the skin, called keratinocytes, move in from the edges of the wound to close the gap. This helps to restore the skin barrier. Previous research has shown that the mechanical forces experienced by keratinocytes play a role in wound closure. Several proteins, called mechanosensors, perceive these forces and instruct the cells what to do. Until now, it was unclear what kind of mechanosensors control wound healing. To find out more, Holt et al. studied a recently discovered mechanosensor (for which co-author Ardem Pataputian received the Nobel Prize in 2021), called Piezo1, using genetically engineered mice. The experiments revealed that skin wounds in mice without Piezo1 in their keratinocytes healed faster than mice with normal levels of Piezo1. In contrast, skin wounds of mice with increased levels of Piezo1 in their keratinocytes healed slower than mice with normal levels of Piezo1. The same pattern held true for keratinocytes grown in the laboratory that had been treated with chemicals to increase the activity of Piezo1. To better understand how Piezo1 slows wound healing, Holt et al. tracked its location inside the keratinocytes. This revealed that the position of Piezo1 changes over time. It builds up near the edge of the wound in some places, and at those regions makes the cells move backwards rather than forwards. In extreme cases, an increased activity of Piezo1 can cause an opening of the wound instead of closing it. These findings have the potential to guide research into new wound treatments. But first, scientists must confirm that blocking Piezo1 would not cause side effects, like reducing the sensation of touch. Moreover, it would be interesting to see if Piezo1 also plays a role in other important processes, such as development or certain diseases.

Mechanobiology of neural development.

As the brain develops, proliferating cells organize into structures, differentiate, migrate, extrude long processes, and connect with other cells. These biological processes produce mechanical forces that further shape cellular dynamics and organ patterning. A major unanswered question in developmental biology is how the mechanical forces produced during development are detected and transduced by cells to impact biochemical and genetic programs of development. This gap in knowledge stems from a lack of understanding of the molecular players of cellular mechanics and an absence of techniques for measuring and manipulating mechanical forces in tissue. In this review article, we examine recent advances that are beginning to clear these bottlenecks and highlight results from new approaches that reveal the role of mechanical forces in neurodevelopmental processes.

Myosin-II mediated traction forces evoke localized Piezo1-dependent Ca2+ flickers.

Piezo channels transduce mechanical stimuli into electrical and chemical signals to powerfully influence development, tissue homeostasis, and regeneration. Studies on Piezo1 have largely focused on transduction of "outside-in" mechanical forces, and its response to internal, cell-generated forces remains poorly understood. Here, using measurements of endogenous Piezo1 activity and traction forces in native cellular conditions, we show that cellular traction forces generate spatially-restricted Piezo1-mediated Ca2+ flickers in the absence of externally-applied mechanical forces. Although Piezo1 channels diffuse readily in the plasma membrane and are widely distributed across the cell, their flicker activity is enriched near force-producing adhesions. The mechanical force that activates Piezo1 arises from Myosin II phosphorylation by Myosin Light Chain Kinase. We propose that Piezo1 Ca2+ flickers allow spatial segregation of mechanotransduction events, and that mobility allows Piezo1 channels to explore a large number of mechanical microdomains and thus respond to a greater diversity of mechanical cues.