Biology subjects

Adler, D.

Publications and source records attributed to Adler, D..

5 recordsLinked to original sources

bioRxiv2026

Functional border-associated macrophages limit Alzheimer's Disease progression

Brain-resident macrophages are known to play numerous roles in the progression of Alzheimers Disease (AD). However, the relative contribution of microglia and border-associated macrophages (BAM) to AD pathogenesis has been difficult to disentangle. We recently identified Maf, a newly described AD GWAS gene, as essential for BAM, but not microglial, survival. By crossing BAM depleted mice with the 5xFAD AD model, we found stark evidence of cerebral amyloid angiopathy (CAA), increased overall {beta}-amyloid burden, accelerated markers of neurodegeneration, and early memory deficits. In the healthy brain, BAM take up more {beta}-amyloid per cell than microglia. However, as disease progresses, both in human AD patient samples and model AD mice, BAM number is reduced, and the remaining BAMs display impaired endocytic capacity, and show signs of metabolic exhaustion at an earlier age than microglia. Thus, strategies to preserve or restore BAM function represents a novel therapeutic avenue for AD and CAA.

immunology↗

bioRxiv2026

Tau-induced ribosomal collisions impair memory through the activation of the integrated stress response

The formation of new long-term memories is reliant upon the spatial and temporal regulation of mRNA translation. Translational control has been demonstrated to be disrupted in neurodegenerative diseases, which exhibit impairments in both homeostatic translation and memory formation, such as Alzheimers disease (AD) and frontotemporal dementia (FTD). However, the precise mechanisms by which this dysregulation occurs, as well as the pathogenic consequences of this dysregulation have yet to be described. Here we establish that FTD-associated tau mutations impair protein synthesis prior to the onset of memory impairments by slowing ribosomal elongation speed, causing ribosomes to collide upon mRNAs. We reveal that this tau-induced ribosomal collision ultimately impairs memory-associated translation through activation of the integrated stress response (ISR) via GCN2. Pharmacological prevention of this ISR activation not only rescues memory formation in the PS19 mouse model of FTD, but also attenuates neuronal death, decreases tau phosphorylation and accumulation, and improves survival. Collectively, our data elucidates a novel mechanism by which mRNA translation is impaired early in neurodegeneration, identifies several pathological phenotypes which are traceable to impairments in mRNA translation, and highlights the therapeutic potential of rescuing these translational impairments.

neuroscience↗

bioRxiv2025

Microglia coordinate activity-dependent protein synthesis in neurons through metabolic coupling

De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here we demonstrate that microglia, resident macrophages of the brain, coordinate metabolic coupling between endothelial cells, astrocytes, and neurons to fuel protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, increasing glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit required for on-demand protein synthesis in mouse motor cortex.

neuroscience↗

bioRxiv2025

Mapping the spatiotemporal dynamics of de novo protein synthesis during long-term memory formation

The formation of new associative long-term memory (LTM) following Pavlovian conditioning is dependent upon multiple, temporally distinct windows of mRNA translation. Current methods lack the temporal specificity to robustly characterize the dynamics of protein synthesis throughout the rodent brain following conditioning. Here we resolve these technological limitations and demonstrate that in awake mice, the retro-orbital (RO) injection of azidohomoalanine (AHA) enables the labelling and subsequent visualization of the brain de novo proteome, with labelling periods as short as 30 minutes. Combining this advancement in de novo proteomic labelling with tissue clearing, we identified brain region, cell-type, and neuronal sub-population specific changes in de novo protein synthesis in mice following an auditory threat conditioning paradigm. This approach also allowed us to track the changes in de novo protein synthesis over time, revealing that conditioning-induced changes in mRNA translation exhibit remarkable temporal specificity in brain regions such as the somatosensory cortex. Taken together, our findings highlight how this novel labelling technique can be used to map the highly intricate temporal and spatial dynamics of mRNA translation after behavioral conditioning.

neuroscience↗

bioRxiv2024

A Reproducibility Focused Meta-Analysis Method for Single-Cell Transcriptomic Case-Control Studies Uncovers Robust Differentially Expressed Genes

We assessed the reproducibility of differentially expressed genes (DEGs) in previously published Alzheimers (AD), Parkinsons (PD), Huntingtons (HD), Schizophrenia (SCZ), and COVID-19 scRNA-seq studies. While transcriptional scores from DEGs of individual PD, HD, and COVID-19 datasets had moderate predictive power for case-control status of other datasets, genes from individual AD and SCZ datasets had poor predictive power. We developed a non-parametric meta-analysis method, SumRank, based on reproducibility of relative differential expression ranks across datasets, and found DEGs with improved predictive power. By multiple metrics, specificity and sensitivity of these genes were substantially higher than those discovered by dataset merging and inverse variance weighted p-value aggregation methods and had significant enrichment in snATAC-seq peaks and human disease gene associations. The DEGs revealed known and novel biological pathways, such as up-regulation of chaperone-mediated protein processing in PD glia and lipid transport in AD and PD microglia, and down-regulation of glutamatergic processes in AD astrocytes and glutamatergic neurons and synaptic processing and neuron projection genes in HD FOXP2 neurons. We find 56 DEGs shared amongst AD, PD, and HD, and validate BCAT1 as down-regulated in AD mouse oligodendrocytes. Lastly, we evaluate factors influencing reproducibility of individual studies as a prospective guide for experimental design.

genomics↗