Biology subjects

Fowler, A. M.

Publications and source records attributed to Fowler, A. M..

4 recordsLinked to original sources

bioRxiv2026

MicroRNA-223 Enhances Microglia-Dependent Clearance of Amyloid Beta Plaques and Ameliorates Behavioral Deficits in a Mouse Model of Alzheimer's Disease

The Alzheimers disease (AD) brain is characterized by dysregulated expression of multiple microRNAs (miRNA), positioning them as promising diagnostic and therapeutic targets. The levels of glia-enriched miR-223 are abnormal in the brains and plasma of AD patients and miR-223 is neuroprotective in models of stroke. However, whether miR-223 can be beneficial in AD is not known. Here, we report that intracerebroventricular (ICV) injection of miR-223 oligonucleotide mimic alleviated cognitive impairment, reduced amyloid beta (A{beta}) pathology, and ameliorated the defects in synaptic marker expression in AppNL-G-F AD model mice. Mechanistically, miR-223 induced microglial clustering around A{beta} plaques with a concomitant upregulation of microglial phagocytic receptors AXL, TREM2 and CD11c, while pharmacological microglial depletion abolished the plaque-clearance phenotype. Moreover, in human iPSC-derived microglia miR-223 directly targeted multiple genes in the endo-lysosomal pathway, including AD risk gene SPPL2A, indicating that it acts as a major regulator of microglial phenotype. Lastly, long-term AAV-mediated overexpression of miR-223 recapitulates its beneficial effects on cognition, pathology, and synaptic marker expression. Our study demonstrates a novel approach for the treatment of AD using miR-223 and highlights the potential of RNAi-based therapeutics in neurodegenerative disease.

neuroscience↗

bioRxiv2026

Defining the DNA Binding Specificity of GRHL2

Grainyhead-like 2 (GRHL2) is an epithelial transcription factor with context-dependent regulatory roles, yet the sequence rules governing its DNA recognition remain incompletely defined. In this study, a high-density genomic Specificity and Affinity for Protein (SNAP) DNA-binding array containing 772,732 tiled probes derived from GRHL2 ChIP-seq regions was used to resolve GRHL2 binding specificity at 6 base pair resolution across genomic sequences. From high-affinity probes, de novo motif analysis recovered the canonical 5-AACCGGTT-3 motif. Sequence specificity landscapes revealed a stepwise reduction in binding as mismatches were introduced, with the strongest effects at the C (position 3) and G (position 6) within the motif, greater tolerance at the central CG dinucleotide, and intermediate tolerance at the A/T bases at the motif edges. This analysis also demonstrated the influence of nearby flanking sequences. Extended motif and spacing analyses indicated dimeric binding at paired motifs, with periodic helical spacing consistent with interactions on the same face of the DNA helix. Integration of SNAP array binding with ChIP-seq data distinguished direct, motif-encoded GRHL2 occupancy from indirect, cofactor-mediated recruitment at genomic sites. These results define the sequence specificity of GRHL2 interactions with variations in the DNA consensus motif and flanking sequences within an endogenous genomic context. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/719077v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@237363org.highwire.dtl.DTLVardef@16c97d7org.highwire.dtl.DTLVardef@64b251org.highwire.dtl.DTLVardef@f72090_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Spatiotemporal Characterization of Amyloidosis-Associated Microglial States Reveals Sex Difference in Early Plaque Formation

Twice as many women develop Alzheimer's disease (AD) compared to men. Several key aspects, such as genetic risk factors, hormonal vulnerability, social responsibilities, and differences in longevity, contribute to the strong female bias in AD. To assess whether sex differences can be detected during the onset of AD, we examined the amyloid-{beta} (A{beta}) plaque burden--one of the hallmarks of AD--and microglial states in young 5XFAD mouse models of amyloid pathology. We hypothesized that an elevated A{beta} burden will directly correlate with an increase in microglial cell number and phagocytic activity, shaping the appearance of compact dense-core plaques in the cortex from 2 to 6 months of age. As expected, no change in microglial density and phenotype was found in A{beta} plaque-free hypothalamus of 5XFAD male and female mice when compared to age-matched wildtype controls. By quantifying the number and coverage of diffuse and dense-core plaques in the cortex, we discovered a pronounced increase in A{beta} plaques and microglial clustering in 4-month-old female 5XFAD compared to male mice. Conversely by 6 months, higher total plaque load in males and no sex difference in the number of plaque-associated microglial (PAM) cluster was observed. Our spatiotemporal characterization of microglial CD68, Dectin-1 (Clec7a), and CD11c (Itgax) expression revealed transient sex differences in the upregulation of only CD68 among these phagocytic markers in cortical microglia. In 4-months-old males, greater phagolysosomal activity may benefit A{beta} clearance and delay plaque formation. In females, lower microglial phagolysosomal activity and increased microgliosis may have led to the increase in plaque deposition and compaction from 2-4 months. Our results suggest that during early amyloidosis, sex differences in CD68-associated phagolysosomal activity and microglia-driven plaque compaction may cause disproportionate AD risk and severity that is compounded by other exacerbating factors during aging. Taken together, sex-specific targeting of microglial proliferation and phagocytic activity may be a promising intervention in presymptomatic patients with known AD risks.

neuroscience↗

bioRxiv2024

Overwintering performance of juvenile temperate estuarine fish

Estuaries, rich in biodiversity and economically valuable species, are increasingly threatened by climate change-induced factors that challenge fish resilience and survival. This study compared the performance of estuarine fishes between water temperatures reflecting two scenarios: current Sydney winters (16{degrees}C) and future winters under climate change (20{degrees}C), and at two food levels, for three estuarine fish species (eastern fortescue, Centropogon australis, common silverbiddy, Gerres subfasciatus, and eastern striped trumpeter, Pelates sexlineatus) Overall, as expected from metabolic theory, fish performance was generally higher at higher temperatures, with growth rates higher at 20{degrees}C for G. subfasciatus and C. australis. Bite rates and aerobic scope were generally higher at the higher temperature for all species. G. subfasciatus and P. sexlineatus exhibited increased escape responses at 20{degrees}C, with P. sexlineatus also showing greater boldness. Boldness was positively associated with bite rates in P. sexlineatus, potentially indicating foraging advantages under future warming for this species. The order of temperature treatment (20{degrees}C then 16{degrees}C, vs 16{degrees}C then 20{degrees}C) affected boldness for G. subfasciatus and growth rate, total length, bite rate and burst speed for P. sexlineatus. Contrary to expectations, food had no effect on fish performance either directly or interacting with temperature, and all three species generally performed better at 20{degrees}C than 16{degrees}C, suggesting this study was conducted below the species thermal optima. Future climate change may therefore favour temperate estuarine fishes at winter temperatures, with potential benefits differing among these species.

ecology↗