IU Indianapolis ScholarWorks :: Browsing by Author "Lin, Peter Bor-Chian"

Browsing by Author "Lin, Peter Bor-Chian"

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Corrigendum: Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2*R47H
(Frontiers Media, 2022-02-07) Kotredes, Kevin P.; Oblak, Adrian; Pandey, Ravi S.; Lin, Peter Bor-Chian; Garceau, Dylan; Williams, Harriet; Uyar, Asli; O’Rourke, Rita; O’Rourke, Sarah; Ingraham, Cynthia; Bednarczyk, Daria; Belanger, Melisa; Cope, Zackary; Foley, Kate E.; Logsdon, Benjamin A.; Mangravite, Lara M.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Carter, Gregory W.; Sasner, Michael; Lamb, Bruce T.; Howell, Gareth R.; Pharmacology and Toxicology, School of Medicine
An author name was incorrectly spelled as “Daria Bednarycek”. The correct spelling is “Daria Bednarczyk”. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Aβ amyloidosis
(American Association for the Advancement of Science, 2021-11) Karahan, Hande; Smith, Daniel C.; Kim, Byungwook; Dabin, Luke C.; Al-Amin, Md Mamun; Wijeratne, H.R. Sagara; Pennington, Taylor; di Prisco, Gonzalo Viana; McCord, Brianne; Lin, Peter Bor-Chian; Li, Yuxin; Peng, Junmin; Oblak, Adrian L.; Chu, Shaoyou; Atwood, Brady K.; Kim, Jungsu; Medical and Molecular Genetics, School of Medicine
Recently, large-scale human genetics studies identified a rare coding variant in the ABI3 gene that is associated with an increased risk of Alzheimer’s disease (AD). However, pathways by which ABI3 contributes to the pathogenesis of AD are unknown. To address this question, we determined whether loss of ABI3 function affects pathological features of AD in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases amyloid β (Aβ) accumulation and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in 5XFAD;Abi3 knockout (“Abi3−/−”) mice. Moreover, we identified marked changes in the proportion of microglia subpopulations in Abi3−/− mice using a single-cell RNA sequencing approach. Mechanistic studies demonstrate that Abi3 knockdown in microglia impairs migration and phagocytosis. Together, our study provides the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting Aβ accumulation and neuroinflammation.
Genetic Variants of Phospholipase C-γ2 Alter the Phenotype and Function of Microglia and Confer Differential Risk for Alzheimer’s Disease
(Elsevier, 2023) Tsai, Andy P.; Dong, Chuanpeng; Lin, Peter Bor-Chian; Oblak, Adrian L.; Di Prisco, Gonzalo Viana; Wang, Nian; Hajicek, Nicole; Carr, Adam J.; Lendy, Emma K.; Hahn, Oliver; Atkins, Micaiah; Foltz, Aulden G.; Patel, Jheel; Xu, Guixiang; Moutinho, Miguel; Sondek, John; Zhang, Qisheng; Mesecar, Andrew D.; Liu, Yunlong; Atwood, Brady K.; Wyss-Coray, Tony; Nho, Kwangsik; Bissel, Stephanie J.; Lamb, Bruce T.; Landreth, Gary E.; Medical and Molecular Genetics, School of Medicine
Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.
In vivo validation of late-onset Alzheimer's disease genetic risk factors
(bioRxiv, 2023-12-24) Sasner, Michael; Preuss, Christoph; Pandey, Ravi S.; Uyar, Asli; Garceau, Dylan; Kotredes, Kevin P.; Williams, Harriet; Oblak, Adrian L.; Lin, Peter Bor-Chian; Perkins, Bridget; Soni, Disha; Ingraham, Cindy; Lee-Gosselin, Audrey; Lamb, Bruce T.; Howell, Gareth R.; Carter, Gregory W.; Radiology and Imaging Sciences, School of Medicine
Introduction: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. Methods: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE4 and Trem2*R47H. Potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. Results: We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. Discussion: These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics.
INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer’s disease
(Wiley, 2023) Lin, Peter Bor-Chian; Tsai, Andy Po-Yi; Soni, Disha; Lee-Gosselin, Audrey; Moutinho, Miguel; Puntambekar, Shweta S.; Landreth, Gary E.; Lamb, Bruce T.; Oblak, Adrian L.; Anatomy, Cell Biology and Physiology, School of Medicine
Introduction: Inositol polyphosphate-5-phosphatase (INPP5D) is a microglia-enriched lipid phosphatase in the central nervous system. A non-coding variant (rs35349669) in INPP5D increases the risk for Alzheimer's disease (AD), and elevated INPP5D expression is associated with increased plaque deposition. INPP5D negatively regulates signaling via several microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2); however, the impact of INPP5D inhibition on AD pathology remains unclear. Methods: We used the 5xFAD mouse model of amyloidosis to assess how Inpp5d haplodeficiency regulates amyloid pathogenesis. Results: Inpp5d haplodeficiency perturbs the microglial intracellular signaling pathways regulating the immune response, including phagocytosis and clearing of amyloid beta (Aβ). It is important to note that Inpp5d haploinsufficiency leads to the preservation of cognitive function. Spatial transcriptomic analysis revealed that pathways altered by Inpp5d haploinsufficiency are related to synaptic regulation and immune cell activation. Conclusion: These data demonstrate that Inpp5d haplodeficiency enhances microglial functions by increasing plaque clearance and preserves cognitive abilities in 5xFAD mice. Inhibition of INPP5D is a potential therapeutic strategy for AD.
Moderate Ethanol Pre-treatment Mitigates ICH-Induced Injury via ER Stress Modulation in Rats
(Frontiers Media, 2021-06-25) Lin, Peter Bor-Chian; Wang, Po-Kai; Pang, Cheng-Yoong; Hu, Wei-Fen; Tsai, Andy Po-Yi; Oblak, Adrian L.; Liew, Hock-Kean; Radiology and Imaging Sciences, School of Medicine
Intracerebral hemorrhage (ICH) is a life-threatening type of stroke that disrupts the normal neurological function of the brain. Clinical studies have reported a non-linear J-shaped association between alcohol consumption levels and the occurrence of cerebral stroke. Specifically, alcohol intoxication increases stroke incidence, while moderate alcohol pre-conditioning decreases stroke frequency and improves outcomes. Although alcohol pre-consumption is likely a crucial player in ICH, the underlying mechanism remains unclear. We performed 1-h alcohol pre-conditioning followed by ICH induction in Sprague-Dawley (SD) rats to investigate the role of alcohol pre-conditioning in ICH. Interestingly, behavioral test analysis found that ethanol intoxication (3 g/kg) aggravated ICH-induced neurological deficits, but moderate ethanol pre-conditioning (0.75 g/kg) ameliorated ICH-induced neurological deficits by reducing the oxidative stress and proinflammatory cytokines release. Moreover, we found that moderate ethanol pretreatment improved the striatal endoplasmic reticulum (ER) homeostasis by increasing the chaperone protein expression and reducing oxidative stress and apoptosis caused by ICH. Our findings show that the mechanism regulated by moderate ethanol pre-conditioning might be beneficial for ICH, indicating the importance of ER homeostasis, oxidative stress, and differential cytokines release in ICH.
Molecular diagnosis and therapy for Plasmodium ovale infection of a returned traveler from East Africa
(Elsevier, 2021-05-06) Tseng, Yu-Chuan; Chang, Yu-Chang; Lee, Chihyi; Hsu, Shih-Fen; Chang, Pai-Chuan; Hsu, Jen-Jen; Lin, Peter Bor-Chian; Lu, Min-Chi; Tien, Ni; Hsiao, Chiung-Tzu; Medicine, School of Medicine
Malaria is an infectious disease caused by Plasmodium parasites that are mainly transmitted through the bites of infected female Anopheles mosquitoes. The average annual number of malaria cases was less than ten in Taiwan in the last five years. Most of the cases were caused by Plasmodium vivax and Plasmodium falciparum, and were primarily diagnosed in travelers who returned from Southeast Asia and Africa. Here, we report the first case of Plasmodium ovale infection within five years that was confirmed by peripheral blood smear examination and molecular identification in a 25-year-old Asian female patient who returned from Uganda.
PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer's disease
(Springer, 2022-02-18) Tsai, Andy P.; Dong, Chuanpeng; Lin, Peter Bor-Chian; Messenger, Evan J.; Casali, Brad T.; Moutinho, Miguel; Liu, Yunlong; Oblak, Adrian L.; Lamb, Bruce T.; Landreth, Gary E.; Bissel, Stephanie J.; Nho, Kwangsik; Medical and Molecular Genetics, School of Medicine
Background Alzheimer’s disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Accumulating evidence from genetic studies suggests the importance of phospholipase C γ 2 (PLCG2) in late-onset AD (LOAD) pathophysiology. However, the role of PLCG2 in AD is still poorly understood. Methods Using bulk RNA-Seq (N=1249) data from the Accelerating Medicines Partnership-Alzheimer’s Disease Consortium (AMP-AD), we investigated whether PLCG2 expression increased in the brains of LOAD patients. We also evaluated the relationship between PLCG2 expression levels, amyloid plaque density, and expression levels of microglia specific markers (AIF1 and TMEM119). Finally, we investigated the longitudinal changes of PLCG2 expression in the 5xFAD mouse model of AD. To further understand the role of PLCG2 in different signaling pathways, differential gene expression and co-expression network analyses were performed using bulk RNA-Seq and microglial single-cell RNA-Seq data. To substantiate the human analyses, we performed differential gene expression analysis on wild-type (WT) and inactivated Plcg2 mice and used immunostaining to determine if the differentially expressed genes/pathways were altered by microglial cell coverage or morphology. Results We observed significant upregulation of PLCG2 expression in three brain regions of LOAD patients and significant positive correlation of PLCG2 expression with amyloid plaque density. These findings in the human brain were validated in the 5xFAD amyloid mouse model, which showed disease progression-dependent increases in Plcg2 expression associated with amyloid pathology. Of note, increased Plcg2 expression levels in 5xFAD mice were abolished by reducing microglia. Furthermore, using bulk RNA-Seq data, we performed differential expression analysis by comparing cognitively normal older adults (CN) with 75th percentile (high) and 25th percentile (low) PLCG2 gene expression levels to identify pathways related to inflammation and the inflammatory response. The findings in the human brain were validated by differential expression analyses between WT and plcg2 inactivated mice. PLCG2 co-expression network analysis of microglial single-cell RNA-Seq data identified pathways related to the inflammatory response including regulation of I-kappaB/NF-kappa B signaling and response to lipopolysaccharide. Conclusions Our results provide further evidence that PLCG2 plays an important role in AD pathophysiology and may be a potential target for microglia-targeted AD therapies.
The Role of Urocortins in Intracerebral Hemorrhage
(MDPI, 2020-01) Choy, KerWoon; Tsai, Andy Po-Yi; Lin, Peter Bor-Chian; Wu, Meng-Yu; Lee, Chihyi; Alias, Aspalilah; Pang, Cheng-Yoong; Liew, Hock-Kean; Neurology, School of Medicine
Intracerebral hemorrhage (ICH) causes an accumulation of blood in the brain parenchyma that disrupts the normal neurological function of the brain. Despite extensive clinical trials, no medical or surgical therapy has shown to be effective in managing ICH, resulting in a poor prognosis for the patients. Urocortin (UCN) is a 40-amino-acid endogenous neuropeptide that belongs to the corticotropin-releasing hormone (CRH) family. The effect of UCN is activated by binding to two G-protein coupled receptors, CRH-R1 and CRH-R2, which are expressed in brain neurons and glial cells in various brain regions. Current research has shown that UCN exerts neuroprotective effects in ICH models via anti-inflammatory effects, which generally reduced brain edema and reduced blood-brain barrier disruption. These effects gradually help in the improvement of the neurological outcome, and thus, UCN may be a potential therapeutic target in the treatment of ICH. This review summarizes the data published to date on the role of UCN in ICH and the possible protective mechanisms underlined.
The Role of INPP5D in Microglial Function and Amyloid Pathogenesis
(2023-07) Lin, Peter Bor-Chian; Block, Michelle L.; Oblak, Adrian L.; Landreth, Gary E.; Kim, Jungsu; Territo, Paul R.
Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia. Genetic studies implicate the involvement of microglia-mediated immune responses during disease progression. Importantly, inositol polyphosphate-5-phosphatase D (INPP5D) serves as a regulator of microglial functions and its variants have been identified as risk of late-onset AD. The primary object of this thesis was to study the role of INPP5D in AD pathogenesis. First, increased levels of INPP5D were detected in brain regions of LOAD patients, and a positive association was noted between INPP5D expression and amyloid plaque density. Importantly, increased INPP5D expression was also observed in the amyloidogenic 5xFAD mouse model, with a similar pattern of elevated expression predominately in plaque-associated microglia. These results demonstrated that INPP5D plays an important role in AD. Second, we determined the effect of Inpp5d haplodeficiency on amyloid pathology and microglial functions in 5xFAD mice. The results revealed that Inpp5d haploinsufficiency reduced amyloid plaque burdens and reversed behavioral deficits in 5xFAD mice. Inpp5d haploinsufficiency enhanced microglial engagement to plaques while increasing amyloid plaque compaction in the brains. Furthermore, Inpp5d haploinsufficiency activates TREM2 signaling and suppresses proinflammatory cytokines release in cortical tissues. Spatial transcriptomic analysis highlights that Inpp5d haploinsufficiency modulated the functional pathways including immune cell activation, cytokines production, protein degradation, memory, and synaptic plasticity. Our study suggests that reducing INPP5D expression alters microglial responses and mitigates amyloid pathology during AD progression. Finally, we prepared primary microglial cultures from the wild-type and Inpp5d-haplodeficient mice. The microglial cultures were treated with fibrillar beta-amyloid (fAβ) to investigate the effect of INPP5D inhibition on microglial signaling. Our results demonstrate an increased fAβ uptake and decreased fAβ cytotoxicity in the Inpp5d-deficient microglia. Inpp5d haplodeficiency alters microglial functional pathways, including phagocytosis, apoptosis, cytokines production, and the complement system. Importantly, Inpp5d haplodeficiency elevates the expression of homeostatic microglia signatures. Furthermore, treatment of microglia with INPP5D antagonist (TAD32, 1 μM) showed similar effect as the Inpp5d deficiency in microglia. Collectively, our study validates the hypothesis that INPP5D inhibition may help protect against AD pathology. Treatments utilizing INPP5D antagonists to target microglia-mediated immune responses may be beneficial as an AD therapy.

Browsing by Author "Lin, Peter Bor-Chian"

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