About

Masashi Kitazawa is an Associate Professor at the University of California, Irvine, affiliated with the Center for Occupational and Environmental Health (COEH) in the School of Medicine, the Joe C. Wen School of Population & Public Health, and the Institute for Memory Impairments and Neurological Disorders (UCI MIND). He earned his Ph.D. in Toxicology from Iowa State University in 2003, following an M.S. in Environmental Toxicology from the University of California, Irvine, and a B.S. in Chemistry from California State University, San Bernardino. His research primarily focuses on understanding the molecular pathogenesis of neurodegenerative diseases, particularly Alzheimer's disease (AD), with an emphasis on the role of neuroinflammation triggered by both endogenous factors such as aging and exogenous environmental factors including chronic exposure to environmental chemicals and toxicants. Kitazawa's laboratory employs multiple experimental platforms, including transgenic mouse models, primary and established cell cultures, and organotypic slices, to investigate dysregulated cellular signaling cascades in microglia and astrocytes during the early phases of AD. His work explores how environmental risk factors like air pollution and inflammation contribute to disease progression, aiming to elucidate mechanisms underlying microglial and astrocyte dysfunction in neurodegeneration. Throughout his career, Kitazawa has been recognized with several awards, including the 2019 Excellence in Graduate Teaching Award from UCI's School of Medicine and the 2015 Senate Award for Distinguished Early Career Research at UC Merced. His research contributions have advanced the understanding of how environmental exposures and immune system disruptions intersect to influence Alzheimer's disease pathology and cognitive decline.

Research topics

• Neuroscience
• Biology
• Medicine
• Genetics
• Pathology
• Internal medicine
• Immunology
• Cell biology

Selected publications

• Generation of humanized TREM2 and hTREM2‐R47H mouse lines and their effects on disease pathogenesis in 5xFAD mice

  Alzheimer s & Dementia · 2025-12-01

  articleOpen access

  BACKGROUND: The TREM2 R47H (rs75932628) coding variant has been identified as one of the most strongly associated genetic risk factors for late-onset Alzheimer's disease (LOAD). Previous studies revealed that this missense mutation causes microglia to be less reactive to the amyloid beta (Aβ) plaques, which might exacerbate the progression of Alzheimer's disease (AD) pathologies. In an effort to develop mouse models for LOAD, we have generated human TREM2 (hTREM2) knock-in and hTREM2-R47H knock-in mouse lines, fully replacing the murine Trem2 (mTrem2) sequence with its human TREM2 counterpart between start and stop codons, and crossed them with 5xFAD mouse line, a commonly used AD mouse model with robust amyloid-beta pathology. We anticipate that these mouse models will shed light on the impact of microglial TREM2-R47H variant in AD pathology development. METHOD: 6 genotype groups were developed (WT, WT;hTREM2, WT;hTREM2-R47H, 5xFAD, 5xFAD;hTREM2, 5xFAD;hTREM2-R47H) with two age time points (4mo, 12mo). Mouse brains were isolated and cut in half; one hemisphere for immunohistochemistry (IHC) and the other for spatial transcriptomic analysis. Amyloid pathology and glial responses were measured via IHC. In spatial transcriptomic analysis using CosMx, transcriptomic characteristics and changes in each glial cell type were analyzed. RESULT: At 4 months of age, 5xFAD mice with the hTREM2-R47H variant showed increased amyloid plaque load in subiculum, and a significant spread of amyloid plaque burden in cortex area relative to both 5xFAD with murine Trem2, as well as with hTREM2. Microglia also failed to respond to plaques. CosMx results indicated that hTREM2-R47H knock-in microglia failed to downregulate homeostatic gene expression (i.e., P2ry12, Csf1r, Tgfbr1, and Tmem119) compared to hTREM2 knock-in line. CONCLUSION: Microglial reactivity to amyloid plaques was less in hTREM2 knock-in line compared to mTrem2, suggesting that hTREM2 itself is not fully functional in the murine biologic system. Nevertheless, compared to mTrem2 and hTREM2, hTREM2-R47H microglia do not down-regulate their homeostatic genes in response to amyloid-beta. Further, the magnitude of the effect of R47H in hTREM2 appears stronger than R47H in mTREM2, suggesting that humanization of disease relevant genes offers additional insights into disease mechanisms.

  PublisherOA PDFDOI

• Regulation of human sodium-dependent vitamin C transporter-2 function in neuronal cells by ubiquitin E3 ligase Nedd4-1

  Physiology · 2023-05-01

  articleOpen access

  The ubiquitin pathway regulates the functional expression of several transporters in many cellular systems. However, currently, nothing is known about the role of ubiquitination E3 ligase, neural precursor cell expressed developmentally down-regulated gene 4 (Nedd4-1) in regulating human vitamin C transporter-2 (hSVCT2, the product of the SLC23A2 gene) in neuronal cells. Nedd4-1 has been identified as a putative interactor with hSVCT2 and in the brain, hSVCT2 is predominantly expressed and mediates the cellular uptake of ascorbic acid (AA). Our aim in this investigation was to address this issue using in vitro (SH-SY5Y and HEK-293 cells), and in vivo (mouse) models, together with an array of physiological, cellular and molecular biological approaches. The results showed that the expression of Nedd4-1 in neuronal samples (human and mouse hippocampi and SH-SY5Y cells) is markedly higher than that of Nedd4-2. Interestingly, Nedd4-1 expression was shown to be significantly higher in the hippocampi of patients with Alzheimer’s disease (AD) and a J20 mouse model of AD. In addition, Nedd4-1-GFP and hSVCT2-DsRed co-localized in intracellular vesicles and at the cell membrane in HEK-293 cells. Further, the co-expression of Nedd4-1 with hSVCT2 showed a marked decrease in AA uptake. In contrast, Nedd4-1 siRNA knockdown significantly increased the AA uptake. Further, we have mutated a classical Nedd4 protein interacting motif (‘PPXY’) within the hSVCT2 polypeptide and observed significantly reduced AA uptake due to the intracellular retention of the hSVCT2 mutant compared to hSVCT2 wild-type. Collectively, our data demonstrate that Nedd4-1 dependent ubiquitination regulates hSVCT2 functional expression in neuronal cells. Supported by NIH grant DK 107474 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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• Exposure to quasi-ultrafine particulate matter accelerates memory impairment and Alzheimer’s disease-like neuropathology in the <i>AppNL-G-F</i> knock-in mouse model

  Toxicological Sciences · 2023-04-19 · 12 citations

  articleOpen accessSenior author

  Exposure to traffic-related air pollution consisting of particulate matter (PM) is associated with cognitive decline leading to Alzheimer's disease (AD). In this study, we sought to examine the neurotoxic effects of exposure to ultrafine PM and how it exacerbates neuronal loss and AD-like neuropathology in wildtype (WT) mice and a knock-in mouse model of AD (AppNL-G-F/+-KI) when the exposure occurs at a prepathologic stage or at a later age with the presence of neuropathology. AppNL-G-F/+-KI and WT mice were exposed to concentrated ultrafine PM from local ambient air in Irvine, California, for 12 weeks, starting at 3 or 9 months of age. Particulate matter-exposed animals received concentrated ultrafine PM up to 8 times above the ambient levels, whereas control animals were exposed to purified air. Particulate matter exposure resulted in a marked impairment of memory tasks in prepathologic AppNL-G-F/+-KI mice without measurable changes in amyloid-β pathology, synaptic degeneration, and neuroinflammation. At aged, both WT and AppNL-G-F/+-KI mice exposed to PM showed a significant memory impairment along with neuronal loss. In AppNL-G-F/+-KI mice, we also detected an increased amyloid-β buildup and potentially harmful glial activation including ferritin-positive microglia and C3-positive astrocytes. Such glial activation could promote the cascade of degenerative consequences in the brain. Our results suggest that exposure to PM impairs cognitive function at both ages while exacerbation of AD-related pathology and neuronal loss may depend on the stage of pathology, aging, and/or state of glial activation. Further studies will be required to unveil the neurotoxic role of glial activation activated by PM exposure.

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• Nedd4-1 regulates human sodium-dependent vitamin C transporter-2 functional expression in neuronal and epithelial cells

  The Journal of Nutritional Biochemistry · 2023-07-07 · 1 citations

  articleOpen access
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• Valproic acid upregulates sodium-dependent vitamin C transporter-2 functional expression in neuronal cells

  Life Sciences · 2022-09-09 · 5 citations

  article
  PublisherDOI

• Learning differentially increases the synaptic levels of AMPA receptor subunits (GluA1‐GluA4) in the rodent hippocampus: a single‐synapse approach

  Alzheimer s & Dementia · 2022-12-01 · 1 citations

  article

  Abstract Background Decades of experimental work support the idea that synapses are the anatomical substrate for experience‐dependent plasticity in the brain. Changes in the synaptic strength underlie learning and memory via the accumulation of glutamate AMPA receptors (AMPAR) at the surface of excitatory synapses. AMPAR are tetrameric receptors constituted by multiple combination of four subunits: GluA1 GluA2, GluA3, and GluA4. However, the relative contribution of each AMPAR subunit on learning and memory is relatively unexplored. Method Here, we introduce Fluorescence Analysis of Single‐Synapse Potentiation induced by Learning (FASS‐PiL), a flow cytometry‐based method to quantify surface levels of all four GluA‐AMPAR subunits, in parallel, in isolated synaptosomes after a learning episode in rodents. We evaluated surface levels of all four AMPAR subunits in synaptosomes of mice trained in a learning protocol commonly used for studying episodic memory in the hippocampus (e.g., Object Location Memory (OLM) and Object Recognition Memory (ORM) tasks). Briefly, after exploring novel objects in a novel environment for 10 min, mice were returned to their home cage for 60 min. After hippocampus dissection, synaptosome isolation, and immunostaining, samples were analyzed via flow cytometry. Result We first demonstrated that FASS‐PiL is a simple and sensitive method to track all four GluAs at the synaptosome surface (each GluA subunit was paired with the presynaptic marker Neurexin‐1beta to focus on synaptosome particles containing both pre‐ and postsynaptic compartments). Notably, by profiling hundreds of events, our data showed that the OLM training increases the number of hippocampal synaptosomes expressing high levels of GluA1 and GluA2, but not GluA3 and GluA4 (vs control animals). Conclusion Our results indicate that plasticity‐related mechanisms underlying learning are AMPA‐subunit‐specific in hippocampal synapses. Our approach could provide the basis for protocols to study behavioral‐relevant mechanisms of plasticity directly at the synapse, with single‐event resolution.

  PublisherDOI

• Angiotensin receptor blockade with olmesartan alleviates brain pathology in obese <scp>OLETF</scp> rats

  Clinical and Experimental Pharmacology and Physiology · 2022-11-18 · 11 citations

  articleOpen accessSenior authorCorresponding

  Metabolic syndrome (MetS) is a rapidly increasing health concern during midlife and is an emerging risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD). While angiotensin receptor blockers (ARB) are widely used for MetS-associated hypertension and kidney disease, its therapeutic potential in the brain during MetS are not well-described. Here, we tested whether treatment with ARB could alleviate the brain pathology and inflammation associated with MetS using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. Here, we report that chronic ARB treatment with olmesartan (10 mg/kg/day by oral gavage for 6 weeks) partially but significantly ameliorated accumulation of oxidized and ubiquitinated proteins, astrogliosis and transformation to neurotoxic astrocytes in the brain of old OLETF rats, which otherwise exhibit the progression of these pathological hallmarks associated with MetS. Additionally, olmesartan treatment restored claudin-5 and ZO-1, markers of the structural integrity of the blood-brain barrier as well as synaptic protein PSD-95, which were otherwise decreased in old OLETF rats, particularly in the hippocampus, a critical region in cognition, memory and AD. These data demonstrate that the progression of MetS in OLETF rats is associated with deterioration of various aspects of neuronal integrity that may manifest neurodegenerative conditions and that overactivation of angiotensin receptor directly or indirectly contributes to these detriments. Thus, olmesartan treatment may slow or delay the onset of degenerative process in the brain and subsequent neurological disorders associated with MetS.

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• Supplementary Material for: Synbindin Downregulation Participates in Slit Diaphragm Dysfunction

  Figshare · 2021-01-01

  datasetOpen access

  <b><i>Introduction:</i></b> Synbindin, originally identified as a neuronal cytoplasmic molecule, was found in glomeruli. The cDNA subtractive hybridization technique showed the mRNA expression of synbindin in glomeruli was downregulated in puromycin aminonucleoside (PAN) nephropathy, a mimic of minimal-change nephrotic syndrome. <b><i>Methods:</i></b> The expression of synbindin in podocytes was analyzed in normal rats and 2 types of rat nephrotic models, anti-nephrin antibody-induced nephropathy, a pure slit diaphragm injury model, and PAN nephropathy, by immunohistochemical analysis and RT-PCR techniques. To elucidate the function of synbindin, a gene silencing study with human cultured podocytes was performed. <b><i>Results:</i></b> Synbindin was mainly expressed at the slit diaphragm area of glomerular epithelial cells (podocytes). In both nephrotic models, decreased mRNA expression and the altered staining of synbindin were already detected at the early phase when proteinuria and the altered staining of nephrin, a key molecule of slit diaphragm, were not detected yet. Synbindin staining was clearly reduced when severe proteinuria was observed. When the cultured podocytes were treated with siRNA for synbindin, the cell changed to a round shape, and filamentous actin structure was clearly altered. The expression of ephrin-B1, a transmembrane protein at slit diaphragm, was clearly lowered, and synaptic vesicle-associated protein 2B (SV2B) was upregulated in the synbindin knockdown cells. <b><i>Conclusion:</i></b> Synbindin participates in maintaining foot processes and slit diaphragm as a downstream molecule of SV2B-mediated vesicle transport. Synbindin downregulation participates in slit diaphragm dysfunction. Synbindin can be an early marker to detect podocyte injury.

  PublisherDOI

• Effect of Lipopolysaccharide and TNF<i>α</i> on Neuronal Ascorbic Acid Uptake

  Mediators of Inflammation · 2021-01-01 · 10 citations

  articleOpen access

  Vitamin C (ascorbic acid: AA) uptake in neurons occurs via the sodium‐dependent vitamin C transporter‐2 (SVCT2), which is highly expressed in the central nervous system (CNS). During chronic neuroinflammation or infection, CNS levels of lipopolysaccharide (LPS) and LPS‐induced tumor necrosis factor‐ α (TNF α ) are increased. Elevated levels of LPS and TNF α have been associated with neurodegenerative diseases together with reduced levels of AA. However, little is known about the impacts of LPS and TNF α on neuronal AA uptake. The objective of this study was to examine the effect of LPS and TNF α on SVCT2 expression and function using in vitro and in vivo approaches. Treatment of SH‐SY5Y cells with either LPS or TNF α inhibited AA uptake. This reduced uptake was associated with a significant decrease in SVCT2 protein and mRNA levels. In vivo exposure to LPS or TNF α also decreased SVCT2 protein and mRNA levels in mouse brains. Both LPS and TNF α decreased SLC23A2 promoter activity. Further, the inhibitory effect of LPS on a minimal SLC23A2 promoter was attenuated when either the binding site for the transcription factor Sp1 was mutated or cells were treated with the NF‐ κ B inhibitor, celastrol. We conclude that inflammatory signals suppress AA uptake by impairing SLC23A2 transcription through opposing regulation of Sp1 and NF‐ κ B factors.

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• Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology

  Nature Communications · 2021 · 113 citations

  • Biology
  • Genetics
  • Neuroscience

  The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules.

  PublisherDOI

Recent grants

• Environmental copper exposure and its impact on microglial Abeta clearance

  NIH · $2.7M · 2014–2020

• Mechanisms of particulate matter-induced neurotoxicity and cognitive decline in mice

  NIH · $414k · 2018–2021

• NIH Grant R00AR054695

  NIH · $714k · 2016

• Neurotoxicity of particulate matter and its interaction with APOE in neurodegeneration

  NIH · $2.2M · 2022–2025

• NIH Grant K99AR054695

  NIH · $165k · 2012

Frequent coauthors

• Frank M. LaFerla

  University of California, Irvine

  44 shared

• Carlos J. Rodríguez‐Ortiz

  Center for Environmental Health

  36 shared

• Masaki Tanemura

  Nagoya Institute of Technology

  36 shared

• Rodrigo Medeiros

  University of California, Irvine

  26 shared

• David Baglietto‐Vargas

  22 shared

• Ryo Ohta

  22 shared

• Sharon Lim

  Broomfield Hospital

  17 shared

• Shuichi Takeda

  Okayama University

  15 shared

Education

• Ph.D., Environmental Health Sciences

  University of California, Los Angeles

  1995

• M.S., Environmental Health Sciences

  University of California, Los Angeles

  1991

• B.S., Environmental Health Sciences

  University of California, Los Angeles

  1989