Biology subjects

LaRocca, T. J.

Publications and source records attributed to LaRocca, T. J..

4 recordsLinked to original sources

bioRxiv2026

Apigenin Improves Healthspan and Protects Against Alzheimer's Disease-Associated Proteotoxicity in C. elegans

Apigenin is an abundant, bioactive phytochemical with reported therapeutic potential and neuroprotective effects in a variety of age-related disease models. However, the extent to which apigenin may promote healthspan and protect against neurodegeneration-associated proteotoxicity has not been thoroughly investigated, and the biological processes/mechanisms that underlie its protective effects remain unclear. To determine if apigenin increases healthspan, we performed lifespan assays in conjunction with measures of aging-relevant physiological function in wild-type C. elegans. We found that chronic exposure to apigenin extended median lifespan and improved multiple readouts of healthspan, including pharyngeal pumping, locomotor activity, and age-related macromolecular damage accumulation. Additional analyses of transgenic reporter strains and transcriptomic profiling (RNA-seq) indicated that apigenin primarily modulated redox-sensitive stress signaling and pathways associated with cellular homeostasis in aging animals. Finally, in transgenic C. elegans strains expressing the pathological Alzheimer's disease-associated proteins amyloid-beta or tau, we found that apigenin had similar beneficial effects on lifespan, healthspan, and proteotoxicity-associated functional impairments. Together, our results support apigenin as a potential healthspan-promoting intervention that acts in part through reductions in oxidative stress-associated signaling, with beneficial effects that extend to models of Alzheimer's disease-associated proteotoxicity.

neuroscience↗

bioRxiv2026

Mitochondrial double-stranded RNA accumulation in brain aging and Alzheimer's disease

Mitochondria and inflammation are tightly linked in aging and Alzheimers disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using human brain tissue and complementary in vitro transcriptomic datasets, quantifying mitochondrial transcripts and dsRNA editing. We found that mt-dsRNA accumulated after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt-dsRNA-driven inflammation. In AD brains, mt-dsRNA accumulation was further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration by identifying mt-dsRNA as a potential driver of chronic inflammation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/703345v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@81f384org.highwire.dtl.DTLVardef@19a8138org.highwire.dtl.DTLVardef@99b597org.highwire.dtl.DTLVardef@1610120_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimers disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-{kappa}B and NLRP3 signaling axis. However, current treatments targeting NF-{kappa}B or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. In this study, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-{kappa}B and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old (aged 19 months) wildtype mice, and in rTg4510 tau pathology mice (aged 2 months). We found that 4 weeks of NF-{kappa}B/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and rTg4510 mice. These effects of NF-{kappa}B/NLRP3-targeting Nanoligomers were also associated with reduced glial cell activation and pathology, favorable changes in transcriptome signatures of glia-associated inflammation (reduced) and neuronal health (increased), and positive systemic effects. Collectively, our results provide a basis for future translational studies targeting both NF-{kappa}B and NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegeneration.

physiology↗

bioRxiv2020

Amyloid beta acts synergistically as a pro-inflammatory cytokine

The amyloid beta (A{beta}) peptide is believed to play a central role in Alzheimers disease (AD), the most common age-related neurodegenerative disorder. However, the natural, evolutionarily-selected functions of A{beta} are incompletely understood. Here, we report that nanomolar concentrations of A{beta} act synergistically with known cytokines to promote pro-inflammatory activation in primary human astrocytes (a cell type increasingly implicated in brain aging and AD). Using transcriptomics (RNA-seq), we show that A{beta} can directly substitute for the complement component C1q in a cytokine cocktail previously shown to induce astrocyte immune activation. Furthermore, we show that astrocytes synergistically activated by A{beta} have a transcriptional signature similar to neurotoxic "A1" astrocytes known to accumulate with age and in AD. Interestingly, we find that this biological action of A{beta} at low concentrations is distinct from the transcriptome changes induced by the high/supraphysiological doses of A{beta} often used in in vitro studies. Collectively, our results suggest an important, cytokine-like function for A{beta} and a novel mechanism by which it may directly contribute to the neuroinflammation associated with brain aging and AD.

molecular biology↗