About

Gregory M. Cole is a Professor-in-Residence in the Department of Neurology at UCLA's David Geffen School of Medicine. His research primarily focuses on neurodegenerative diseases, particularly Alzheimer's disease, exploring mechanisms of pathology and potential therapeutic interventions. His work includes investigating tauopathy in mice and humans, surrogate plasma biomarkers for brain trauma-initiated neurodegenerative disease, and modulating innate immune function to prevent age-related neurodegeneration. Dr. Cole has contributed significantly to understanding the biochemical and molecular underpinnings of Alzheimer's, including amyloid pathology, synaptic biomarkers, and neuroinflammation. His research employs a multidisciplinary approach, integrating pharmacogenomics, multiomics analysis, and innovative imaging techniques to identify biomarkers and develop potential treatments for neurodegenerative conditions.

Research topics

• Biochemistry
• Chemistry
• Chromatography
• Psychology
• Genetics
• Medicine
• Clinical psychology
• Biology
• Bioinformatics
• Internal medicine
• Psychiatry

Selected publications

• Integrated Multiomics Analysis of Salivary Exosomes to Identify Biomarkers Associated with Changes in Mood States and Fatigue

  International Journal of Molecular Sciences · 2022 · 11 citations

  • Medicine
  • Bioinformatics
  • Clinical psychology

  Fatigue and other deleterious mood alterations resulting from prolonged efforts such as a long work shift can lead to a decrease in vigilance and cognitive performance, increasing the likelihood of errors during the execution of attention-demanding activities such as piloting an aircraft or performing medical procedures. Thus, a method to rapidly and objectively assess the risk for such cognitive fatigue would be of value. The objective of the study was the identification in saliva-borne exosomes of molecular signals associated with changes in mood and fatigue that may increase the risk of reduced cognitive performance. Using integrated multiomics analysis of exosomes from the saliva of medical residents before and after a 12 h work shift, we observed changes in the abundances of several proteins and miRNAs that were associated with various mood states, and specifically fatigue, as determined by a Profile of Mood States questionnaire. The findings herein point to a promising protein biomarker, phosphoglycerate kinase 1 (PGK1), that was associated with fatigue and displayed changes in abundance in saliva, and we suggest a possible biological mechanism whereby the expression of the PGK1 gene is regulated by miR3185 in response to fatigue. Overall, these data suggest that multiomics analysis of salivary exosomes has merit for identifying novel biomarkers associated with changes in mood states and fatigue. The promising biomarker protein presents an opportunity for the development of a rapid saliva-based test for the assessment of these changes.

  PublisherOA PDFDOI

• A sensitive LC-MS assay using derivatization with boron trifluoride to quantify curcuminoids in biological samples

  Analytical Biochemistry · 2020 · 9 citations

  • Chemistry
  • Chromatography
  • Biochemistry
  PublisherOA PDFDOI

• Curcumin restores innate immune Alzheimer's disease risk gene expression to ameliorate Alzheimer pathogenesis

  Neurobiology of Disease · 2019-04-02 · 126 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• P3‐187: Neuronally‐Derived Exosomal Proteins Can Predict Brain Amyloidosis

  Alzheimer s & Dementia · 2016-07-01

  article

  Neuronally-derived exosomes (NDE) are vesicles shed by neurons that can be readily extracted from plasma. Exosomal Aβ1-42, P-S396-tau and P-T181-tau levels have high accuracy for discriminating mild cognitive impairment (MCI) and Alzheimer’s dementia (AD) from frontotemporal dementia and normal controls (NC). NDE levels of repressor element 1-silencing transcription factor (REST) are significantly lower while levels of cathepsin D are significantly higher in AD. The post-synaptic protein neurogranin (NRGN) is increased in the CSF and decreased in the cortices of AD patients. CSF neurogranin levels predict progression from MCI to AD. We investigated whether NDE levels of Aβ1-42, P-S396-tau, P-T181-tau, REST, Cathepsin D and NRGN can predict of brain amyloidosis in a cohort of NC, MCI and AD subjects. 37 NC, 19 MCI and 16 AD ImaGene subjects underwent F18–Flutemetamol PET imaging and provided plasma samples for NDE extraction and ELISA quantification. As plasma samples can vary with respect to the NDE content, all protein analyte levels were normalized using NDE CD81 levels. F18–Flutemetamol scans were normalized to cerebellar gray matter and interpreted as positive and negative using the previously validated cut-off of 1.27. Using a support vector machine classifier approach we studied the ability of NDE-derived proteins to predict amyloid PET status in the pooled cohort. In a second iteration we also added APOE4 genotype to investigate if it will further improve the predictive accuracy. Both classifiers included age and gender. The classifier ranked all predictors and iteratively selected those that resulted in the best predictive accuracy. Multiple comparison corrections were conducted by cross-validation with the leave-one-out approach. The first classifier achieved an accuracy of 84.6% (AUC=0.85) using only Cathepsin D and Aβ1-42 (Figure). The addition of APOE4 did not improve classifier accuracy (accuracy=84.7%, AUC=0.81). The best predictors in this model were APOE4, gender, and NRGN as predictors (Figure).

  PublisherDOI

• IC‐P‐057: Neuronally‐Derived Exosomal Proteins Can Predict Brain Amyloidosis

  Alzheimer s & Dementia · 2016-07-01

  article

  Neuronally-derived exosomes (NDE) are vesicles shed by neurons that can be readily extracted from plasma. Exosomal Aβ1-42, P-S396-tau and P-T181-tau levels have high accuracy for discriminating mild cognitive impairment (MCI) and Alzheimer’s dementia (AD) from frontotemporal dementia and normal controls (NC). NDE levels of repressor element 1-silencing transcription factor (REST) are significantly lower while levels of cathepsin D are significantly higher in AD. The post-synaptic protein neurogranin (NRGN) is increased in the CSF and decreased in the cortices of AD patients. CSF neurogranin levels predict progression from MCI to AD. We investigated whether NDE levels of Aβ1-42, P-S396-tau, P-T181-tau, REST, Cathepsin D and NRGN can predict of brain amyloidosis in a cohort of NC, MCI and AD subjects. 37 NC, 19 MCI and 16 AD ImaGene subjects underwent F18–Flutemetamol PET imaging and provided plasma samples for NDE extraction and ELISA quantification. As plasma samples can vary with respect to the NDE content, all protein analyte levels were normalized using NDE CD81 levels. F18–Flutemetamol scans were normalized to cerebellar gray matter and interpreted as positive and negative using the previously validated cut-off of 1.27. Using a support vector machine classifier approach we studied the ability of NDE-derived proteins to predict amyloid PET status in the pooled cohort. In a second iteration we also added APOE4 genotype to investigate if it will further improve the predictive accuracy. Both classifiers included age and gender. The classifier ranked all predictors and iteratively selected those that resulted in the best predictive accuracy. Multiple comparison corrections were conducted by cross-validation with the leave-one-out approach. The first classifier achieved an accuracy of 84.6% (AUC=0.85) using only Cathepsin D and Aβ1-42 (Figure). The addition of APOE4 did not improve classifier accuracy (accuracy=84.7%, AUC=0.81). The best predictors in this model were APOE4, gender, and NRGN as predictors (Figure).

  PublisherDOI

• Apolipoprotein E isotype-dependent modulation of microRNA-146a in plasma and brain

  Neuroreport · 2016-06-10 · 23 citations

  articleOpen accessSenior authorCorresponding

  The Apolipoprotein E (ApoE) isotype ApoE4 is a prevalent genetic risk factor for Alzheimer's disease (AD) that can modulate systemic and central inflammation, independent of amyloid accumulation. Although disruption of innate immune toll receptor signaling is modulated by ApoE and observed in AD, ApoE isotype-specific effects remain poorly understood. Therefore, we examined the effect of the ApoE isotype on the brain levels of major regulators of TLR signaling including miR146a, a microRNA enriched in the brain. We used 6-month-old ApoE3 or ApoE4 targeted replacement mice with and without mutant familial AD transgenes. ApoE4 reduced the levels of miR146a compared with ApoE3, both in the brain (29%; P<0.0001) and in plasma (47%; P<0.05), which correlated with each other (r=0.74; P<0.05). The presence of 5xFAD transgenes increased brain miR146a in both ApoE3 (E3FAD) and ApoE4 (E4FAD) mice; however, miR146a levels in E4FAD mice remained lower than those in E3FAD mice (62%; P<0.05), despite increased amyloid and inflammation. Supporting these observations, ApoE4 brains showed increased expression of interleukin receptor-associated kinase-1 (160%; P<0.05) (normally downregulated by miR146) that correlated inversely with miR146a levels (r=0.637; P<0.0001). Reduced negative feedback of toll-like receptor signaling (by miRNA146a) can explain early-life hypersensitivity to innate immune stimuli (including Aβ) in ApoE4 carriers. Thus, ApoE4 causes early dysregulation of a central controller of the innate immune system both centrally and systemically. This defect persists with familial AD pathology and may be relevant to ApoE4 AD risk.

  PublisherOA PDFDOI

• P3‐147: APOE4‐Dependent Synaptic‐Derived Plasma Biomarkers in Alzheimer's Disease

  Alzheimer s & Dementia · 2016-07-01

  articleSenior author

  Synaptic deficits driven by Abeta oligomers and tau pathology are central to Alzheimer disease (AD) and believed to be reflected in cortical deficits in FDG-PET measures of glucose utilization. FDG-PET deficits similar to those in AD occur early in middle-aged pre-symptomatic ApoE4 carriers and begin as early as 20-39 years of age. Current blood biomarkers appear to reflect complex responses to AD but surrogate markers reflecting early synaptic changes, would be useful to assess synaptic protection with prevention approaches and treatments. We sought evidence for circulating candidate CNS-derived markers with potential to reflect early synaptic pathology including the neuronal pentraxin receptor (NPR) and its ligand, synapse-derived neuronal pentraxin I (NP1). Both NPR and NP1 are involved in glutamate receptor internalization and preferentially expressed in brain. NP1 is normally secreted from presynaptic sites and induced in response to Abeta by activated GSK3beta in brains of AD model mice. 3-month-old amyloid bearing ApoE4x 5FAD (E4FAD) mice (n=7-8) were DHA treated for four months. Blood, brain and plasma exosome NP1, NP1 and NPR fragments were quantified by Western blot. Normal human plasma (n=18 for ApoE3, n=24 for ApoE4) and plasma from 7-8-month-old ApoE4 targeted replacement (E4-TR) mice (n=7-8) were also investigated. We found NP1 and NP1 fragments were increased in both brain and plasma of 7-8 month old amyloid bearing ApoE4x 5FAD (E4FAD) mice that have glutamate receptor loss by 6 months of age. Plasma NP1 and its fragments were significantly correlated with brain NP1. Plasma NPR1 fragments were also increased in E4FAD mice. In these mice, NP1, NP1 and NPR fragments were reduced by DHA treatment and found in plasma neural exosomes. Comparing NP1 between E4FAD and ApoE4 targeted replacement (E4-TR) mice without 5FAD, plasma NP1 was reduced in E4-TR mice, suggesting the modulation of NP1 by Abeta. Finally, plasma NP1 was elevated in aging cognitively normal human APOE4 carriers at risk for AD (but not in AD) suggesting involvement in excitatory synapse loss that occurs in prodromal disease. NP1, NP1 and NPR fragments may be potential ApoE4 isoform-dependent excitatory neuron derived plasma biomarkers relevant to early synaptic alterations.

  PublisherDOI

• O5‐05‐05: CSF proteomic discovery in persons with autosomal dominant Alzheimer's disease mutations

  Alzheimer s & Dementia · 2015-07-01

  article

  The identification of protein differences in the cerebrospinal fluid (CSF) from individuals with incipient or early Alzheimer's disease (AD) may assist in both early diagnosis and the identification of novel therapeutic targets. Proteomic CSF studies in individuals carrying fully-penetrant autosomal dominant Alzheimer's Disease (ADAD) mutations provide the opportunity to identify early changes in persons in whom the future diagnosis of AD is certain. We performed clinical evaluations and obtained CSF from 43 individuals either symptomatic from ADAD mutations (n=18, CDR = 0.5 in 12) or at 50% risk for inheriting such mutations (n=25). Among the 31 mutation carriers (MCs), 26 had PSEN1 mutations and 5 had the V717I APP mutation. CSF was depleted of 14 high abundance proteins, digested with trypsin and the resulting peptides were analyzed by liquid chromatography-mass spectrometry (LCMS). Peptides were identified by shotgun sequencing and clustered into their parent proteins. Peptide peaks were aligned across all samples and peak intensities were measured and compared to determine relative peptide and protein abundance in each sample. Protein levels were separately compared between mutation non-carriers (NCs, n=12) versus all ADAD MCs and versus all presymptomatic MCs (n=13). 1,018 proteins were differentially quantified and identified. Using an intensity difference of 2-fold, and p- and q-values (false discovery rate) of 0.05 as cut-offs for significance, we identified 12 proteins that were differentially expressed between ADAD MCs and NCs. Thrombospondin-2, LRP 11, NPDC1, Complement factor H, Fibronectin, Complement component C7, Transcription factor SOX-13, Clusterin, Fatty acid-binding protein, and APP were increased and Folate receptor alpha and CRP were decreased in ADAD MCs. An additional 22 proteins were differentially expressed with significant but smaller differences. When only presymptomatic ADAD mutation carriers were included, no protein was expressed with a 2-fold difference and only one (LRP1) was elevated with p- and q-values 0.05. Proteins associated with the cell matrix, inflammation, vascular remodeling, and Abeta transport are elevated in ADAD MCs Only LRP1 was elevated in presymptomatic MCs, suggesting that its overexpression represents an adaptive response to Abeta overproduction.

  PublisherDOI

• Clinical development of curcumin in neurodegenerative disease

  Expert Review of Neurotherapeutics · 2015-06-02 · 177 citations

  reviewOpen access

  Curcumin, a polyphenolic antioxidant derived from the turmeric root has undergone extensive preclinical development, showing remarkable efficacy in wound repair, cancer and inflammatory disorders. This review addresses the rationale for its use in neurodegenerative disease, particularly Alzheimer’s disease (AD). Curcumin is a pleiotropic molecule, which not only directly binds to and limits aggregation of the β-sheet conformations of amyloid characteristic of many neurodegenerative diseases but also restores homeostasis of the inflammatory system, boosts the heat shock system to enhance clearance of toxic aggregates, scavenges free radicals, chelates iron and induces anti-oxidant response elements. Although curcumin corrects dysregulation of multiple pathways, it may exert many effects via a few molecular targets. Pharmaceutical development of natural compounds like curcumin and synthetic derivatives have strong scientific rationale, but will require overcoming various hurdles including; high cost of trials, concern about profitability and misconceptions about drug specificity, stability and bioavailability.

  PublisherOA PDFDOI

• Alzheimer risk genes modulate the relationship between plasma apoE and cortical PiB binding

  Neurology Genetics · 2015-10-01 · 16 citations

  articleOpen access

  OBJECTIVE: We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association. METHODS: Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) participants with available [(11)C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes. RESULTS: Low plasma apoE was significantly associated with high PiB SUVR, except in the sensorimotor and entorhinal cortex. For BIN1 rs744373, the association was observed only in minor allele carriers. For CD2AP rs9349407 and CR1 rs3818361, the association was preserved only in minor allele noncarriers. We did not find evidence for modulation by CLU, PICALM, ABCA7, BIN1, and MS4A6A. CONCLUSIONS: Our data show that BIN1 rs744373, CD2AP rs9349407, and CR1 rs3818361 genotypes modulate the association between apoE protein plasma levels and brain amyloidosis, implying a potential epigenetic/downstream interaction.

  PublisherOA PDFDOI

Recent grants

• NIH Grant RC1AG035878

  NIH · $1.0M · 2012

• NIH Grant R01AG011125

  NIH · $298k · 1996

• NIH Grant I01BX000542

  NIH · 2013

• NIH Grant R01AG009009

  NIH · $697k · 1997

• NIH Grant R01AG013741

  NIH · $2.5M · 2012

Frequent coauthors

• Sally A. Frautschy

  VA Greater Los Angeles Healthcare System

  298 shared

• Fusheng Yang

  143 shared

• Qiu‐Lan Ma

  University of Southern California

  97 shared

• Bruce Teter

  96 shared

• John Q. Trojanowski

  University of Pennsylvania

  84 shared

• Gabrielle Strobel

  Alzforum

  81 shared

• Donna L. McPhie

  Harvard University

  81 shared

• Sam Sisodia

  McLean Hospital

  81 shared

Education

• M.D.

  University of California, Los Angeles

• B.A.

  University of California, Los Angeles