Publications by authors named "Andrew A Pieper"

Article Synopsis
  • High microglial diversity complicates the creation of targeted treatments for Alzheimer's disease (AD).
  • A comprehensive analysis of RNA-sequencing data revealed specific microglial subtypes associated with AD and identified potential drug targets, including microglial transition networks.
  • The study highlights ketorolac as a promising anti-inflammatory treatment for AD, showing its association with lower AD incidence in patient databases.
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Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. We developed a network medicine methodology via integrating human brain multi-omics data to prioritize drug targets and repurposable treatments for ALS. We leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on human brain expression quantitative trait loci (QTL) (eQTL), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL).

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Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. However, current treatments are directed at symptoms and lack ability to slow or prevent disease progression. Large-scale genome-wide association studies (GWAS) have identified numerous genomic loci associated with PD, which may guide the development of disease-modifying treatments.

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Current pharmacologic treatments for atherosclerosis do not completely protect patients; additional protection can be achieved by dietary modifications, such as a low-cholesterol/low-fat diet (LCLFD), that mediate plaque stabilization and inflammation reduction. However, this lifestyle modification can be challenging for patients. Unfortunately, incomplete understanding of the underlying mechanisms has thwarted efforts to mimic the protective effects of a LCLFD.

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  • Delirium is a fluctuating mental condition that increases risks of long hospital stays, health complications, and death, but diagnosing it objectively is challenging.
  • Recent studies show that bispectral electroencephalography (BSEEG) can effectively diagnose delirium and predict patient outcomes, potentially serving as a vital sign.
  • In experiments with a mouse model, two compounds, P7C3-A20 and minocycline, successfully prevented delirium symptoms caused by infections, while haloperidol did not, suggesting new therapeutic avenues for protecting patients from delirium.
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  • Transposable element (TE) dysregulation is linked to neuroinflammation in Alzheimer's disease (AD) and this study aims to identify TE quantitative trait loci (teQTLs) in the brains of aged individuals with AD.
  • Utilizing large-scale RNA sequencing and whole-genome sequencing data from three human AD brain biobanks, researchers discovered 26,188 significant teQTLs and demonstrated an association between these elements and AD-related genetic factors.
  • Experimental CRISPR interference assays indicated that an upregulated TE affects neuroinflammation by suppressing the expression of the anti-inflammatory gene C1QTNF4 in neurons derived from human induced pluripotent stem cells.
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Progression of acute traumatic brain injury (TBI) into chronic neurodegeneration is a major health problem with no protective treatments. Here, we report that acutely elevated mitochondrial fission after TBI in mice triggers chronic neurodegeneration persisting 17 months later, equivalent to many human decades. We show that increased mitochondrial fission after mouse TBI is related to increased brain levels of mitochondrial fission 1 protein (Fis1) and that brain Fis1 is also elevated in human TBI.

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  • - The study investigated the link between neurocognitive performance and blood levels of GluA1 autoantibodies in NCAA athletes, comparing contact and noncontact sport participants before and after the season.
  • - Contact sport athletes showed a significant increase in serum GluA1 autoantibodies at the end of the season, regardless of concussion status, while noncontact athletes did not exhibit any changes.
  • - Athletes with higher levels of GluA1 autoantibodies had poorer reaction times, indicating cognitive impairment, which suggests that these autoantibodies could serve as a blood-based marker to identify athletes at risk for cognitive issues, even without a concussion.
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  • Tau acetylation at lysine 174 is linked to neurodegenerative diseases like Alzheimer's, FTLD, and TBI, and targeting it could improve cognitive function.
  • In a study using PS19 mice, treatment with anti-ac-tauK174 antibodies reduced tau pathology and improved neurobehavioral outcomes, even after TBI.
  • Results showed that anti-ac-tauK174 not only mitigated memory impairment and neurodegeneration but also altered gene expression in brain cells, indicating its potential as a therapeutic approach for tau-related conditions.
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  • The research identifies the role of gut microbial metabolites in Alzheimer's disease (AD) and focuses on the host's G-protein-coupled receptors (GPCRs) that interact with these metabolites.
  • Using a systems biology framework, the study analyzes 1.09 million metabolite-protein pairs, revealing orphan GPCRs like GPR84 as potential drug targets.
  • The findings show that specific metabolites, such as phenethylamine and agmatine, can reduce tau hyperphosphorylation in neurons linked to AD, highlighting a novel approach to exploring GPCR targets in complex diseases.
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Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. To date, the challenge to establishing effective treatment for ALS remains formidable, partly due to inadequate translation of existing human genetic findings into actionable ALS-specific pathobiology for subsequent therapeutic development. This study evaluates the feasibility of network medicine methodology via integrating human brain-specific multi-omics data to prioritize drug targets and repurposable treatments for ALS.

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Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD.

Objective: To investigate the potential therapeutic benefit of sildenafil on AD.

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Biliverdin reductase-A (BVRA) is a multi-functional enzyme with a multitude of important roles in physiologic redox homeostasis. Classically, BVRA is well known for converting the heme metabolite biliverdin to bilirubin, which is a potent antioxidant in both the periphery and the brain. However, BVRA additionally participates in many neuroprotective signaling cascades in the brain that preserve cognition.

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The high failure rate of clinical trials in Alzheimer's disease (AD) and AD-related dementia (ADRD) is due to a lack of understanding of the pathophysiology of disease, and this deficit may be addressed by applying artificial intelligence (AI) to "big data" to rapidly and effectively expand therapeutic development efforts. Recent accelerations in computing power and availability of big data, including electronic health records and multi-omics profiles, have converged to provide opportunities for scientific discovery and treatment development. Here, we review the potential utility of applying AI approaches to big data for discovery of disease-modifying medicines for AD/ADRD.

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Alpha-synuclein has been implicated in neurodegenerative diseases such as Parkinson's disease and dementia with Lewy bodies, with A53T and A30P mutations shown to be disease causing. It has been reported that hemizygous transgenic mice with tyrosine hydroxylase promotor-driven expression of A53T/A30P mutant alpha-synuclein in dopamine neurons provide a useful preclinical model of these conditions by virtue of developing behavioral deficits. Here, we report a lack of replication of this finding.

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Introduction: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood.

Methods: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort.

Results: We identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression.

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Traumatic brain injury (TBI) is a leading worldwide cause of disability, and there are currently no medicines that prevent, reduce, or reverse acute or chronic neurodegeneration in TBI patients. Here, we review the target-agnostic discovery of nicotinamide adenine dinucleotide (NAD)/NADH-stabilizing P7C3 compounds through a phenotypic screen in mice and describe how P7C3 compounds have been applied to advance understanding of the pathophysiology and potential treatment of TBI. We summarize how P7C3 compounds have been shown across multiple laboratories to mitigate disease progression safely and effectively in a broad range of preclinical models of disease related to impaired NAD/NADH metabolism, including acute and chronic TBI, and note the reported safety and neuroprotective efficacy of P7C3 compounds in nonhuman primates.

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Oxidative damage in the brain is one of the earliest drivers of pathology in Alzheimer's disease (AD) and related dementias, both preceding and exacerbating clinical symptoms. In response to oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) is normally activated to protect the brain from oxidative damage. However, Nrf2-mediated defense against oxidative stress declines in AD, rendering the brain increasingly vulnerable to oxidative damage.

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The gaseous neurotransmitter hydrogen sulfide (H S) exerts neuroprotective efficacy in the brain via post-translational modification of cysteine residues by sulfhydration, also known as persulfidation. This process is comparable in biological impact to phosphorylation and mediates a variety of signalling events. Unlike conventional neurotransmitters, H S cannot be stored in vesicles due to its gaseous nature.

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Traumatic brain injury (TBI)-induced axonal degeneration leads to acute and chronic neuropsychiatric impairment, neuronal death, and accelerated neurodegenerative diseases of aging, including Alzheimer's and Parkinson's diseases. In laboratory models, axonal degeneration is traditionally studied through comprehensive postmortem histological evaluation of axonal integrity at multiple time points. This requires large numbers of animals to power for statistical significance.

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The gaseous signaling molecule hydrogen sulfide (HS) critically modulates a plethora of physiological processes across evolutionary boundaries. These include responses to stress and other neuromodulatory effects that are typically dysregulated in aging, disease, and injury. HS has a particularly prominent role in modulating neuronal health and survival under both normal and pathologic conditions.

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Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by which TBI increases the risk of developing aging-related neurodegenerative disease, however, are not completely understood.

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