Biology subjects

Figueiredo-Pereira, M. E.

Publications and source records attributed to Figueiredo-Pereira, M. E..

3 recordsLinked to original sources

bioRxiv2023

Diazoxide/dibenozylmethane treatment mitigates spatial memory deficits and pathology and up regulates protective genes in an Alzheimer's transgenic rat model

INTRODUCTIONAlzheimers disease (AD) is a multifactorial disease for which therapeutic efficacy should benefit from a multi-target approach. Thus, we evaluated a combined chronic treatment with diazoxide (DZ) and dibenzoylmethane (DIB). DZ is a potassium channel activator. DIB counteract eIF2-P-driven stress responses. The individual therapeutic benefits of each drug on attenuating neurodegeneration and apoptosis were previously examined, but not as a combined treatment. METHODSWe evaluated the efficacy of chronic DZ/DIB treatment on TgF344-AD rats (Tg-AD) at 4- and 11-months of age and wild-type littermates. Spatial working memory was assessed with the radial 8-arm maze, and AD pathology by immunohistochemistry. We used RNA sequencing for transcriptome analysis. RESULTSDZ/DIB-treatment mitigated the spatial memory deficits as well as the buildup of hippocampal A{beta} plaques and tau PHF exhibited by 11-month Tg-AD rats. The DZ/DIB-treatment had no effect on wild-type littermates. We did not detect AD-related deficits in untreated 4-month Tg-AD rats, but DZ/DIB-treatment altered their transcriptome. DZ/DIB-treatment of 4-month Tg-AD rats upregulated several genes normally downregulated in AD and/or aging. Expression of two potential early biomarkers for AD, EGR2 (early growth response 2) and HISIT1H2AA (histone H2AA), were also altered by the DZ/DIB treatment in 4-month Tg-AD rats. The treatment reduced levels of eIF2, a protein involved in abnormal translational repression and a contributing factor to neuronal loss. DISCUSSIONThis preclinical study represents the first report on the combined DZ/DIB-treatment. Besides the benefits of this treatment on spatial memory and AD pathology, we identified two potential early AD biomarkers. Furthermore, the DZ/DIB-treatment prevented downregulation of genes associated with AD and/or aging. Overall, our results strongly support that the combination DZ/DIB-treatment mitigates AD pathology. Evaluations across multiple AD-related models are warranted to further corroborate that the DZ/DIB combination is a candidate treatment for AD. HighlightsO_LIDZ/DIB treatment improves cognitive deficits and AD pathology in TgF344-AD rats C_LIO_LIEGR2 and HISIT1H2AA genes are potential early AD biomarkers in TgF344-AD rats C_LIO_LIDZ/DIB treatment of 4-month TgF344-AD rats blocks downregulation of AD/aging genes C_LI RESEARCH IN CONTEXT1. Systematic Review: We reviewed the literature using traditional sources (e.g., PubMed) to assess the status of DZ and DIB treatment individually in preclinical studies in animal models. To our knowledge there is no data with this chronic combined treatment. 2. Interpretation: Treatment takes advantage of a polypharmacological approach to AD therapeutics, considering the multifactorial nature of AD. DZ and DIB individually have been successful in mitigating hippocampal AD pathology but their combined effects were unknown, particularly in a rodent model that shows a more complete disease progression that incorporates aging as a risk factor. The effects of the treatment go beyond previous data in individual DZ and DIB treatment, supporting the need for combination drug treatments to treat a multifactorial disorder. 3. Future Directions: Investigate the potential of DZ/DIB treatment to stop the progression or ameliorate AD pathology when administered at a later age, when pathology is first detected. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=138 HEIGHT=200 SRC="FIGDIR/small/555966v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@7cc6a0org.highwire.dtl.DTLVardef@1d468feorg.highwire.dtl.DTLVardef@390f19org.highwire.dtl.DTLVardef@e40c8_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Prostaglandin D2 pathway in a transgenic rat model of Alzheimer's disease: therapeutic potential of timapiprant a DP2 antagonist

The cyclooxygenase pathway, a key mediator of inflammation, is implicated in Alzheimers disease (AD). A deeper investigation is required into the contributions of this pathway to the neuropathology of AD. Cyclooxygenases produce prostaglandins, which have multiple receptors and functions including inflammation, nociception, sleep, cardiovascular maintenance and reproduction. In the brain, prostaglandin D2 (PGD2) is the most abundant prostaglandin, increases the most under pathological conditions, and plays roles in sleep, stroke and inflammation. PGD2 signals through its DP1 and DP2 receptors and their activation can be protective or detrimental. We address the relationship between the PGD2 pathway and AD neuropathology with F344-AD transgenic (Tg-AD) rats that exhibit age-dependent and progressive pathology similar to AD patients. We analyzed the PGD2 pathway in the hippocampus of wild type (WT) rats and their Tg-AD littermates, at the age of 11 months, when Tg-AD rats exhibit plaques and perform significantly worse in hippocampal-dependent cognitive tasks than WT rats. Using mass spectrometry, we determined that PGD2 levels were at least 14.5-fold higher than PGE2, independently of genotype. Immunohistochemistry established that microglial DP1 receptors were more abundant and neuronal DP2 receptors were fewer in Tg-AD than in WT rats. RNA sequencing profiling of 33 genes involved in the PGD2 and PGE2 pathways revealed that mRNA levels were the highest for L-PGDS, the major PGD2 synthase in the brain. To evaluate the pathophysiological significance of our findings on the PGD2 pathway, we treated a subset of rats (WT and Tg-AD males) with timapiprant, a potent and highly selective oral DP2 antagonist being developed as a once-daily oral treatment in patients with allergic inflammation. We conclusively show that timapiprant significantly mitigated some of the AD pathology exhibited by the Tg-AD male rats. More comprehensive studies are necessary to support the therapeutic potential of timapiprant and that of other PGD2-related compounds in the treatment of AD.

neuroscience↗

bioRxiv2022

Females outperform males in spatial learning despite increased amyloid plaques and microgliosis in a TgF344-AD rat model of Alzheimer's disease

Alzheimers disease (AD) is a progressive neurodegenerative disease and is the sixth leading cause of death in the US. AD is more prevalent in females than males. While estrogen provides neuroprotection in females, sex mediated differences in the development of AD pathology are not fully elucidated. Therefore, a comparison of the events that develop between sexes in the early-stage of AD pathology may reveal new potential targets for more effective therapeutic intervention. To address sex differences, we analyzed early stage 9-month male and female TgF344-AD (Tg-AD) rats, an AD model carrying the APPswe and Presenilin 1 (PS1{Delta}E9) mutations that develops progressive age-dependent AD pathology similar to humans. Using active place avoidance (aPAT) tests that assess hippocampal-dependent spatial learning and memory, we found significant deficits in Tg-AD females compared to wild type females, but no significant difference between the two male genotypes. Moreover, significant sex differences were observed in that Tg-AD females outperformed Tg-AD males in several measures of the aPAT test. Unexpectedly, Tg-AD females displayed higher levels of hippocampal amyloid plaques and amoeboid microglia than their Tg-AD male littermates. Furthermore, Tg-AD females experienced less hippocampal neuronal loss and had higher GluA2 subunit levels than Tg-AD males. Based on our findings, we propose that estrogen may protect females against cognitive impairment at early stages of AD by regulating GluA2 levels independently of amyloid plaque deposition and gliosis. Elucidating this potential protective mechanism of action of estrogen in AD could lead to new targets for early intervention.

neuroscience↗