In the Howell lab, we apply genetics and genomics approaches to identify fundamental processes involved in the initiation and early propagation of age-related neurodegenerative diseases, focusing on Alzheimer's disease, non-Alzheimer's dementia and glaucoma. Understanding these processes and individual susceptibility to them provides the greatest opportunity of therapeutic intervention. We are particularly interested in the role of astrocytes, myeloid-derived cells (such as microglia and macrophages), endothelial cells and pericytes in response to genetic predisposition, lifestyle choices and age.

In previous work, Dr. Howell applied novel genomics and bioinformatics strategies to identify new molecular stages of glaucoma that preceded morphological changes. Genetic knockout and/or pharmaceutical approaches showed that targeting the complement cascade and endothelin system significantly lessened glaucomatous neurodegeneration in mice. Our work with glaucoma continues in collaboration with Dr. Simon John, and we are also now applying similar genetics and genomics strategies to Alzheimer's disease and other dementias. A major aim of the lab is to combine knowledge from human genetic and genomic studies with the strengths of mouse genetics and genome engineering to develop new and improved mouse models for dementias and make them readily available to scientific community.

Scientific report

Identifying critical early events in Alzheimer's disease (AD)
Current mouse models develop AD-related phenotypes such as plaque deposition and glial activation, but the key early events in the pathogenesis of AD have not been studied. Identifying these early processes will provide novel targets to evaluate for human treatments (Figure 1). We are performing gene expression profiling combined with bioinformatics analyses and subsequent functional tests to determine early molecular processes of AD. I first applied this experimental design to glaucoma, where early pathological events were identified and their importance then tested using both gene knockouts and pharmacological intervention.

Bioinformatics approaches are being used to determine genes and biological processes that change early. Gene profiling datasets of this complexity do not currently exist for AD and will greatly facilitate our understanding of molecular changes that occur prior to its traditionally recognized hallmarks. This work is also likely to order processes that are currently known to be involved in AD but whose timing of activation is unclear. Our long-term goal is to determine the beneficial or damaging role(s) that key early events play using genetically engineered mice.

 Amyloid-beta plaques

Figure 1: Amyloid-beta plaques first appear in B6.APBTg mice between four and six months of age. To determine the ideal ages at which to perform gene expression profiling, we used the timeframe of AD phenotype development in the cortex. Plaques were visualized using Thioflavin T (seen in blue). The earliest and smallest plaques appear at four months of age.  

Developing the next generation of more predictive mouse models for Alzheimer’s disease
Standardizing and improving existing mouse models of AD: Animal models of AD have provided important insights into the pathophysiology of disease and suggested potential avenues for therapies. However, translation of these findings to the clinic has been limited. Therefore, to improve existing models, we are performing standardized behavioral testing on the most popular AD models in collaboration with Genetic Resource Sciences at JAX. We are generating APP/PS1 mice on at least eight genetically diverse strain background to assess whether different genetic backgrounds can improve AD-relevant phenotypes (Figure 2).

AD-relevant phenotypes

Figure 2: Phosphorylated Tau is present in D2.APBTg mice. Hyperphosphorylated Tau protein accumulates in neurons. This accumulation is a hallmark phenotype of AD in humans but is rarer in mouse models for AD that overexpress mutant APP and PSEN1. 


Validating genome-wide association hits: Variations in multiple genes are likely to interact to cause late-onset Alzheimer’s disease (LOAD). Hundreds of genes have been associated with LOAD, with meta-analysis significantly associating dozens of them. However, for most genes, definitive role(s) in Alzheimer’s disease have not been identified. Endocytosis is consistently implicated as a key process in AD. APOE, CLU, BIN1, ABCA7, PICALM, CD2AP and SORL1 can be directly linked to endocytosis with additional genes indirectly linked. However, these genes are expressed in multiple cell types and so it is not clear whether disruption to endocytosis in only one cell type, such as in neurons to regulate synaptic function, or in multiple cell types, such as astrocytes and microglia, is a key factor in Alzheimer’s disease. Given that some of the genes involved in endocytosis also function in other processes, it is also possible that variations in these genes impact other aspects of AD, including neuroinflammation and vascular dysfunction.

Identifying novel genes/causative variants for AD: We are working with other investigators at JAX—Dr. Greg Carter, Dr. Michael Stitzel and Dr. Duygu Ucar—to  analyze publicly available human genome sequences relevant to AD, including the Alzheimer’s disease sequencing project (ADSP) and Alzheimer’s disease neuroimaging initiative (ADNI), to identify novel variants and loci associated with AD. These putative variants are being engineered in mice using genome editing (CRISPR/cas9) and cohorts of mice aged and phenotyped. We are particularly interested in modeling the heterogeneity of AD by assessing the impact of multiple variants.

Understanding the impact of lifestyle choices in aging and dementia

Exercise improves loss of neurovascular unit decline seen in age
Aging is the major risk factor for cognitive decline and neurodegenerative diseases. We are studying the impact of aging on vascular compromise and whether these changes predispose individuals to neurodegenerative disease such as AD. In our recent study, transcriptional profiling suggested genes involved in the maintenance of the neurovascular unit altered with age. We confirmed these changes with histological approaches. Specifically, blood vessels surrounding the basement membrane decreased and coincided with a loss of pericytes (Figure 3). Astrocyte reactivity and microglia activation also increased with age. Previous studies have shown that exercise can have a positive impact on cognition and neuronal function, but its impact on vascular compromise has not been studied. Our data shows that mice that ran voluntarily from middle age to old age showed a marked improvement in neurovascular unit health (NVU), blood brain barrier function, neuronal activity and behavior, and correlated with a decrease in potentially damaging neuroinflammatory molecules including complement component C1QA.

Interestingly, NVU decline was not reversed in APOE deficient mice that already show vascular comprise. This suggests APOE is either a key component of exercise-mediated neurovascular unit preservation or that exercise can prevent but not reverse vascular compromise. Studies are ongoing to determine the factors involved in age-related vascular compromise, the mechanisms by which exercise prevents vascular compromise and the role of APOE in these processes.




Figure 3: Pericytes important to the neurovascular unit lose integrity with age, leading to a breakdown of the blood-brain barrier. Transmission Electron Microscopy shows degeneration of pericytes in aged neurovascular unit (right) as well as thickening of the basement membrane. These pathologies indicate a disfunction in the neurovascular unit, which leads to blood-brain barrier dysfunction. BV = Blood vessel. EC=Endothelial cells. P=Pericyte. DP=Degenerating pericyte.

We are particularly interested in the role of neuroinflammation in aging. We, and others, have shown the complement cascade is upregulated in myeloid cells in aging, and we hypothesize that it may contribute to both neuronal dysfunction (particularly synapse dysfunction) and vascular compromise in aging and very early stages of AD.

A western diet induces chronic neuroinflammation and cognitive deficits
Today, one in three adults in America are obese, a sharp increase since 1950, when only 9% of Americans were obese. Mid-life obesity increases the risk for Alzheimer’s disease and cognitive decline by six-fold, and 20% of Alzheimer’s cases in the U.S. are caused by physical inactivity. It is unknown how the increase in the number of older, obese adults will affect the healthcare system as they age.

Obesity increases the risk of cognitive decline and dementias, but the mechanisms involved are not known. Our data suggests neuroinflammation (inflammation in glial cells such as astrocytes and microglia) is a critical component of obesity-induced cognitive decline. In the brain, astrocytes and microglia are rapid first responders to insults, such as inflammatory cytokines and chemokines. Both astrocytes and microglia are extremely important to brain health, providing nutrients and removing waste from neurons as well as immune surveillance, but they have adverse effects if activated over a sustained period of time (chronic inflammation). Microglia are the brain’s resident macrophage, providing crucial immune responses.

Increased reactive microglia

Figure 4: Increased reactive microglia in the hippocampus of western diet-fed C57BL6/J mice. The neuroinflammatory response to a western diet (WD) can be detrimental to the health of neurons, which can lead to cognitive impairment. Microglia become reactive in response to inflammation and remove waste. Once neuroinflammation becomes chronic, microglial response could be detrimental.

Excessive neuroinflammation can influence communication between the brain and the peripheral immune system during disease states. In some neurodegenerative diseases, including AD, peripheral immune cells, such as monocytes, cross the blood-brain barrier to respond to inflammation. This infiltration of monocytes from the periphery has been shown to cause more damage. Resident microglia can also become chronically inflamed or reactive (Figure 4), which can lead to neuronal impairments, including synapse and myelin loss. We are working to better understand obesity-induced neuroinflammation and peripheral immune cell infiltration into the brain (Figure 5), as well as ways to ameliorate inflammation by exercising or by genetically disrupting monocyte infiltration.


Reactive Monocytes

Figure 5: Increased reactive monocytes in response to western diet (WD) in B6.APBTg mice. The neuroinflammatory response to a western diet can be detrimental to the health of neurons, which can lead to a cognitive impairment. The number of microglia (labeled by IBA1 in red) is increasing in response to WD in the hippocampus. This is likely due to peripheral immune cells infiltrating into the brain in response to inflammatory cytokines. Trem2 (green) is expressed on monocytes/macrophages (including microglia) in environments of severe inflammation, including in neurodegenerative diseases like AD.

Investigating cell specific roles of complement cascade in glaucoma
In addition to our interests in the role of the complement cascade in aging and dementias, we are studying its role in glaucoma, a disease that affects 70 million people. Glaucoma is a leading cause of blindness worldwide, characterized by the loss of retinal ganglion cells (RGCs), the output neurons of the retina. Age and intraocular pressure elevation are major risk factors for glaucoma. Complement expression increases in human glaucoma and in all animal models of glaucoma assessed to date. Our work extended previous studies by showing that induction of the complement cascade occurs very early during glaucoma (in both RGCs and monocyte-derived cells) (Figure 6). We found that DBA/2J mice with a targeted null mutation in the gene for complement component 1qa (C1qa) are robustly protected from glaucoma. The robust protection highlights the importance of determining exactly how the complement cascade influences glaucoma. C1QA is expressed in at least two cell types (RGCs and microglia). Complement component C3 is also expressed in astrocytes. We are functionally testing the importance of C1Q and C3 from neurons, myeloid-derived cells and astrocytes using conditional knockout mice. Determining the significance of complement biosynthesis by each of these cell types is important for designing therapeutic interventions that manipulate the complement system.

Molecular Clustering

Figure 6: Molecular clustering identifies early stages of glaucoma in the retina. Pathway analysis (using DAVID) of differentially expressed genes in two early stages of glaucoma identified the complement cascade as the most significantly over-enriched pathway. Genes shown in red have greater expression in the second molecularly defined retinal stage. The three genes marked by red and bold boxes were differentially expressed in the earliest retinal stage.

Lab staff

Principal Investigator: Gareth Howell, Ph.D.
Associate Research Scientist:  Ileana Soto Reyes, Ph.D.
Postdoctoral Fellow: Kristen Onos, Ph.D.
Research Assistant II: Harriet Williams, B.Sc. 
Research Assistant I: Keating Pepper,B.A.
Laboratory Technician IV: Kelly Keezer
Predoctoral Associate: Leah Graham, B.S.
Research Administrative Assistant: Patricia Cherry

Publication listings

Peer-reviewed papers


Aung T, Ozaki M, Mizoguchi T, et al.  2015. A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. Nat Genet 47(7):387-39. 2

Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller SL, Broihier ML, Xu G, Margevicius D, Karol JC, Sousa GL, Cotleur AC, Butovsky O, Bekris L, Staugaitis SM, Leverenz JB, Pimplikar SW, Landreth GE, Howell GR, Ransohoff RM, Lamb BT. 2015. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med 212(3):287-295. PMCID: PMC4354365


Cross SH, Macalinao DG, McKie L, Rose L, Kearney AL, Rainger J, Thaung C, Keighren M, Jadeja S, West K, Kneeland SC, Smith RS, Howell GR, Young F, Robertson M, van T' Hof R, John SW, Jackson IJ.  A dominant-negative mutation of mouse Lmx1b causes glaucoma and is semi-lethal via LBD1-mediated dimerisation.  PLoS Genet 2014 May 8; 10(5):e1004359. PMCID: PMC4014447

Howell GR, MacNicoll KH, Braine CE, Soto I, Macalinao DG, Sousa GL, John SWM. 2014. Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma. Neurobiol Dis. 71:44-52. PMCID: PMC4319373

Soto I, Howell GR. 2014. The Complex Role of Neuroinflammation in Glaucoma. Cold Spring Harb Perspect Med 4(8)pii: a017269. doi: 10.1101/cshperspect.a017269.

Soto I, Howell GR, John CW, Kief JL, Libby RT, John SWM. 2014. DBA/2J Mice Are Susceptible to Diabetic Nephropathy and Diabetic Exacerbation of IOP Elevation. PLoS ONE 9(9):e107291 PMCID:PMC4160242


Jackson HM, Soto I, Graham LC, Carter GW, Howell GR. 2013. Clustering of transcriptional profiles identifies changes to insulin signaling as an early event in a mouse model of Alzheimer's disease. BMC Genomic Nov 25;14(1):831. PMCID: PMC3907022

Howell GR, Libby RT. 2013. Adding metabolomics to the toolbox for studying retinal disease. Invest Ophthalmol Vis Sci 54(6):4260. Commentary

Howell GR, Soto I, Ryan M, Graham LC, Smith R, John SWM. 2013. Deficiency of complement component 5 ameliorates glaucoma in DBA/2J mice. J Neuroinflammation 10(1):76. PMCID: PMC3708765

Wiggs JL, Howell GR, Linkroum K, Abdrabou W, Hodges E, Braine CE, Pasquale LR, Hannon GJ, Haines JL, John SWM. 2013. Variations in COL15A1 influence age of onset of primary open angle glaucoma. Clin Genet 84(2):167-174. PMCID: PMC3771394

Williams PA, Howell GR, Barbay JM, Braine CE, Sousa GL, John SWM, Morgan JE. 2013. Retinal ganglion cell dendritic atrophy in DBA/2J glaucoma. PLoS One 8(8):e72282. PMCID: PMC3747092.


Howell GR, Soto I, Zhu X, Ryan M, Macalinao DG, Sousa GL, Caddle LB, Harmon K, Barbay JM, Porciatti V, Anderson MG, Smith RS, Clark AF, Libby RT, John SWM. 2012. Radiation treatment inhibits monocyte entry into the optic nerve head and prevents glaucoma in DBA/2J mice. J Clin Invest 122(4):1246-1261. PMCID: PMC3314470

Reinholdt LG*, Howell GR*, Czechanski AM, Macalinao DG, MacNicoll KH, Lin C-S, Donahue LR, John SWM. 2012. Generating embryonic stem cells from the inbred mouse strain DBA/2J, a model of glaucoma and other complex diseases. Plos One 7(11):e50081  PMCID: PMC3507949 *Authors contributed equally. PMCID: PMC3507949

Simon MM, Mallon AM, Howell GR, Reinholdt LG. 2012. High throughput sequencing approaches to mutation discovery in the mouse. Mamm Genome 23(9-10):499-513. PMCID: PMC3724459


Barabas P, Huang W, Chen H, Koehler CL, Howell G, John SWM, Tian N, Renter RC, Krista D. 2011. Missing opt motor head turning reflex in the DBA/2J mouse. IOVS 52(9):6766-6773. PMCID: PMC3175994

Howell GR, Macalinao DR, Sousa G, Walden M, Soto I, Kneeland S, Barbay J, King BL, Marchant JK, Hibbs M, Stevens B, Barres BA, Clark AF, Libby RT, John SWM. 2011. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. 121(4):1429-44. J Clin Invest 121(4):1429-1444. PMCID: PMC3069778

Howell GR, Walton D, King BJ, Libby RT, John SWM. 2011. Datgan: a reusable software system for visualizing transcriptome profiling data. BMC Genomics 14:429. PMCID: PMC3171729

Lachke SA, Alkuraya FS, Kneeland SC, Ohn T, Aboukhalil A, Howell GR, Saadi I, Cavallesco R, Yue Y, Tsai A, Nai S, Cosma MI, Smith RS, Hodges E, Alfadhli SM, Al-Hajeri A, Shamseldin H, Behbehani A, Hannon GJ, Bulyk ML, Drack AV, Anderson P, John SWM, Maas RL. 2011. Mutations in the RNA granule component TDRD7 cause cataract, glaucoma and male sterility. Science 331(6024):1571-1576. PMCID: PMC3279122

Nair KS, Hmani-Aifa M, Ali Z, Kearney A, Salem SB, Macalinao DG, Cosma IM, Bouassida W, Hakim B, Benzina Z, Soto I, Söderkvist P, Howell GR, Smith RS, Ayadi H, John SWM. 2011. Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice. Nat Genet 43(6):579-584. PMCID: Letter


Howell GR, Libby RT, John SW. 2008. Mouse genetic models: an ideal system for understanding glaucomatous neurodegeneration and neuroprotection. Prog Brain Res 173:303-321.


Howell GR, Libby RT, Jakobs TC, Smith RS, Phalan FC, Barter JW, Barbay JM, Marchant JK, Mahesh N, Porciatti V, Whitmore AV, Masland RH, John SW. 2007. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol. 179:1523-37. PMCID: PMC2373494

Howell GR, Libby RT, Marchant JK, Wilson LA, Cosma IM, Smith RS, Anderson MG, John SW. 2007. Absence of glaucoma in DBA/2J mice homozygous for wild-type versions of Gpnmb and Tyrp1. BMC Genet 3:45. PMCID: PMC1937007

Howell GR, Shindo M, Murray S, Gridley T, Wilson LA, Schimenti JC. 2007. Mutation of a ubiquitously expressed mouse transmembrane protein (Tapt1) causes specific skeletal homeotic transformations. Genetics 175(2):699-707. PMCID: PMC1800629

Libby RT, Howell GR, Pang IH, Savinova OV, Mehalow AK, Barter JW, Smith RS, Clark AF, John SW. 2007. Inducible nitric oxide synthase, Nos2, does not mediate optic neuropathy and retinopathy in the DBA/2J glaucoma model. BMC Neurosci 8:108. PMCID: PMC2211487

Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow A, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SWM, Barres BA. 2007. The classical complement cascade mediated CNS synapse elimination. Cell 131:1164-1178.

From 1997 to 2006

Das RM, Van Hateren NJ, Howell GR, Farrell ER et al. 2006. A robust system for RNA interference in the chicken using a modified microRNA operon. Dev Biol 294:554-563.

Howell GR, Bergstrom R, Munroe R, Masse J and Schimenti JC. 2005. Identification of a cryptic lethal mutation in the mouse tw73 haplotype. Genet Res 84(3):153-59.

Howell GR, Munroe RJ and Schimenti JC. 2005. Transgenic rescue of the mouse t complex haplolethal locus Thl1. Mamm Genome 16(11):838-46.

Ross MT, Grafham DV, Scherer S, Coffey J, McLay K, Muzny D, Platzer M, Howell GR, Burrows C et al. 2005. The DNA sequence of the human X chromosome. Nature 434(7031):325-37.

Wilson L, Ching Y-C, Farias M, Hartford S, Howell GR, Shoa H, Bucan M and Schimenti JC. 2005. A region-specific ENU mutagenesis screen on mouse chromosome 5. Genome Res 15(8):1095-105.

Woodward KJ, Cundall M, Sperle K, Sistermans EA, Ross M, Howell GR, et al. 2005. Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. Am J Hum Genet 77(6):966-87.

Mungall AJ et al. 2003. The DNA sequence and analysis of human chromosome 6. Nature 425:805-811.

McMullen TW, Crolla JA, Gregory SG, Carter NP, Cooper RA, Howell GR, Robinson DO. 2002. A candidate gene for congenital bilateral isolated ptosis identified by molecular analysis of a de novo balanced translocation. Human Genetics 110(3):244-250.

Stephan D, Howell GR, Teslovich TM, Coffey AJ, et al. 2002. Physical and transcript map of the hereditary prostate cancer region at Xq27. Genomics 79(1):41-50.

Bentley DB, et al. 2001. The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X. Nature 409(6822):942-3.

Blanco P, Sargent C, Boucher C, Howell G, Ross M, Affara N . 2001. (2001). A novel poly(A)-binding protein gene (PABPC5) maps to an X-specific subinterval in the Xq21.3/YP11.2 homology block of the human sex chromosomes. Genomics 74:1-11.

Braybrook C, Warry G, Howell G, Arnason A, Bjornsson A, Moore G, Ross M, Stanier P. 2001. Identification and characterization of KLHL4, a novel human homologue of the Drosophila Kelch gene that maps within the X-linked cleft palate and Ankyloglossia (CPX) critical region. Genomics 72:128-136.

Carrie A, Jun L, Bienvenu T, Vinet MC, McDonell N, Couvert P, Zemni R, Cardona A, Van Buggenhout G, Frints S, Hamel B, Moraine C, Ropers HH, Strom T, Howell GR, et al. 1999. A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nat Genet 23(1):25-31.

Steingruber HE, Dunham A, Coffey AJ, Clegg SM, Howell GR, Maslen GL, Scott CE, Gwilliam R, Hunt PJ, Sotheran EC, Huckle EJ, Hunt SE, Dhami P, Soderlund C, Leversha MA, Bentley DR, Ross MT. 1999. High-resolution landmark framework for the sequence-ready mapping of Xq23-q26.1. Genome Res 9(8):751-762. PMCID: PMC310799

Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR, et al. 1998. Host responses to EBV infection in X-linked lymphoproliferative results from mutations in an SH2-domain encoding gene. Nat Genet 20(2):129-35.

Gregory SG, Howell GR, Bentley DR. 1997. Genome mapping by fluorescent fingerprinting. Genome Res 79(12):1162-68.

Walpole SM, Nicolaou A, Howell GR, Bentley DR, Ross MT, Yates JR, Trump D. 1997. High-resolution physical map of the X-linked retinoschisis interval in Xp22. Genomics 44(3):300-08.

Books Chapters and Reviews:

Howell GR, Soto I, Libby RT, John SWM. 2012. Intrinsic axonal degeneration pathways are critical for glaucomatous damage. Exp NeurolNickells RW, Howell GR, Soto I, John SWM. 2012. Under pressure: cellular and molecular responses in glaucoma. Annual Reviews of Neuroscience 35:153-179

Howell GR, John SWM. 2010. Genetic and genomic approaches for understanding retinal diseases. Animal models of retinal diseases. Clark AF and Pang I-H (Eds). Springer Protocols.

Howell GR, Marchant JK and John SWM. 2008. Mouse Models: A Key system for revolutionizing understanding of glaucoma. Eye, Retina and Visual System of the Mouse. Chalupa LM and Williams RW (Eds). MIT Press.


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