While neurons are the most studied cells of the central nervous system, a vast majority of the brain is made of specialized cells called ‘glia’. My research interests are to explore the cellular and molecular interactions between neurons and glia under physiological and pathological conditions of neurodevelopment and neurodegeneration. My research is particularly focused on the glial cells--astrocytes and oligodendrocytes. I use transgenic mice and human induced pluripotent stem cell (iPSC) as tools to model and understand disease mechanisms.
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In my current role in drug discovery, I employ glia and neuronal models for finding new therapeutic targets focused on the neurological diseases--
Alzheimer's and Parkinson's disease. My research involves target identification, target validation, lead optimization and biomarker identification. In addition, building PK/PD correlation and new assay and model building for targets.
RESEARCH INTERESTS
Oligogenesis in Spinal cord injury
Tubb4a mutations in
oligodendrocytesÂ
and neurons
Astrocyte dysfunction in ALS
Astrocyte dysfunction in ALS
Astrocyte-mediated neuroinflammation in AGS
Glia and Neuron
dysfunction in leukodystrophies
Role of retro elements in AGS
Oligodendrogenesis in Spinal cord injury (SCI)
My graduate research explored the factors regulating formation of oligodendrocytes especially in context of SCI; as oligodendrocytes die in SCI leading to demyelination. Specifically, I examined the role of a transcription factor Peroxisome Proliferator Activated Receptor (PPAR) and demonstrated that PPAR-delta is elevated and promotes OL differentiation after SCI. I also established that gemfibrozil, an agonist of PPAR-alpha, results in adverse effects in SCI, with potential toxicity related implications for SCI patients.
The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice
Almad A, Lash AT, Wei P, Lovett-Racke AE, McTigue DM. (2011) Experimental Neurology 232 (2): 309-17
Oligodendrocyte fate after spinal cord injury
 Almad A, Sahinkaya FR and McTigue D (2011) Neurotherapeutics8 (2): 262-73
Chronic expression of PPAR-delta by oligodendrocyte lineage cells in the injured rat spinal cord
Almad A and McTigue D (2010)Â Journal of Comparative Neurology 518 (6); 785-99
Does chronic remyelination occur for all spared axons after spinal cord injury in mouse? Â
Gensel JC, Almad A, Alexander JK, Schonberg DL, Tripathi RB. (2008) Journal of Neuroscience 28 (34): 8385-6
Glia In Adult Neurodegenerative Disease
Role of Astrocyte connexins in Amyotrophic Lateral Sclerosis
During my post-doctoral research, I studied the role of astrocytes in ALS, which involves a loss of motor neurons resulting in progressive paralysis and premature death. Astrocytes are key contributors to the disease progression and pathology of ALS. My research examined the molecular mechanisms underlying astrocyte mediated toxicity and led to a new research direction focused on contributions of astrocyte Connexin 43 (Cx43). I discovered the novel role of astrocyte Cx43 hemichannels as conduits of astrocyte-mediated disease progression and highlights Cx43 as a pharmacological target for disease-modifying ALS therapies and a potential biomarker.
Connexin 43 hemichannels mediate spatial and temporal disease spread in Amyotrophic Lateral Sclerosis
Almad A*, Taga A*, Joseph J*, Connor W, Patankar A, Gross S, Richard JP, Pokharel A, Lillo M, Dastgheyb R, Eggan K, Haughey N, Contreras J, and Maragakis N. J Clin Invest., In revision, bioRxiv 2020.03.14.990747
Perfluorocarbon labeling of human glial-restricted progenitors for 19F MRI
Richard JP, Hussain U, Gross S, Taga A, Kouser M, Almad A, Campanelli J, Bulte JWM and Maragakis NJ (2019) Stem Cells Translational Medicine00: -1-11
Serial in vivo imaging of transplanted allogeneic neural stem cell survival in a mouse model of amyotrophic lateral sclerosis
Srivastava A, Gross S, Almad A, Bulte C,  Maragakis N, Bulte J.  (2017) Experimental Neurology289: 96-102
Connexin 43 in astrocytes contributes to motor neuron toxicity in Amyotrophic Lateral Sclerosis
Almad A, Doreswamy A, Gross S, Richard JP, Huo Y, Haughey N and Maragakis N. (2016)Â Glia 64 (7) 1154-1169
Glia: an emerging target for neurological disease therapy
 Almad A and Maragakis N. (2012) Stem Cell Research and Therapy 3:37
Awarded the MSCRF Post-doctoral fellowship (2013-15)
Role: Principal Investigator
Human iPS cell-derived astrocytes to study ALS and astrocyte connexins as a therapeutic target
Glial and Neuronal Dysfunction in Leukodystrophies
Leukodystrophies are rare inherited disorders, involving hallmark features of glial dysfunction along with neuronal or axonal loss. My research is focused on two different leukodystrophies: TUBB4A-associated leukodystrophy and Aicardi Gouteries Syndrome.
Glial cells in the driver seat of Leukodystrophies
Garcia L, Hacker J, SaseS, and Almad A* (2020) Neurobiology of Disease,Special Issue: The roles of glia in neurodegenerative disease 142, 105087. ^corresponding author
Oligodendrocyte and neuronal dysfunction in inherited demyelinating disorders
Tubulin beta class IVA (TUBB4A) is a microtubule (MT) sub-unit, highly expressed in the CNS and primarily localized to oligodendrocytes and neurons. MT are highly dynamic, and essential for neuronal and oligodendrocyte structure, including arborization, polarity, growth cone dynamics, axonal transport and intracellular transport of key proteins. Monoallelic mutations in TUBB4A are known to cause a spectrum of neurologic disorders ranging from an early-onset leukoencephalopathy to adult-onset Dystonia type. Hypomyelination and atrophy of Basal Ganglia and Cerebellum (H-ABC) falls within this spectrum and a single recurrent mutation, p.Asp249Asn, is closely associated with the H-ABC phenotype. We have established a knock-in mouse model, Tubb4aD249N/D249N, displays classic H-ABC phenotypes including progressive gait dysfunction, tremor, ataxia, and decreased survival. These mice also replicate the characteristic hypomyelination and striatal/cerebellar degeneration seen in H-ABC affected individuals. In parallel, I have used reprogrammed human induced Pluripotent Stem cells (iPSC) from control and affected individuals and differentiated them towards neuronal and oligodendrocyte fate. The cells demonstrate decreased survival and reduced arborization.
A novel mouse for modeling of the Classical H-ABCÂ TUBB4AD249N mutation
Sase S*, Almad A*,Boecker A, Li J, Takanohashi A, Patel A, McCaffrey T, Patel H, Sirdeshpande D, Padiath Q, Dias P, Holzbaur E, Scherer S and Vanderver A. (2020) eLife,2020;9: e52986*co-first authors
Awarded the Calliope Joy Foundation grant (2020-21)
Role: Co-Investigator
Anti-sense Oligonucleotide therapy in H-ABC
Awarded the CHOP Cellular and Gene Therapy grant (2020-22)
Role: Co-Investigator
Therapeutic over-expression of Tubb4a in H-ABC
Astrocyte mediated neuroinflammation in Aicardi Gouteries Syndrome
AGS is an autoimmune neurological disorder caused due to mutations that result in production of in activation of the cytokine interferon (IFN) pathway. While a few studies indicate that astrocytes are a source of IFN, their role in AGS has not been studied, especially for ADAR1 mutation. Ongoing work is examining the cellular and molecular mechanisms of astrocyte-mediated neuroinflammation in AGS, using Adar1 transgenic mice and human iPSCs as model systems.
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Astrocytes, an active player in Aicardi- Goutières syndromeÂ
Sase S, Takanohashi A, Vanderver A and Almad A^ (2018) Brain Pathology 28 (3) 399-407 ^corresponding author
Role of retroelements in Aicardi Goutières Syndrome
AGS is caused by mutations in one of seven genes, including ADAR1, which result in an accumulation of immune stimulatory nucleic acids in AGS, causing devastating injury to the CNS due to over-production of IFN. One source of immunostimulatory nucleic acids in AGS are the endogenous retroelements, which replicate through conversion of RNA transcripts into DNA for genomic insertions. Long Interspersed Element class 1 (LINE-1 or L1) are autonomous retroelements that encode its own reverse transcriptase (RT) to replicate RNA into DNA. While, Alu are non-autonomous retroelements that use L1RT function to replicate their DNA. Mutations in the AGS genes TREX1, SAMHD1 and RNASEH2A/ B/C result in increased L1 RT function, causing accumulation of retroelements and activation of IFN pathway. A pilot study6in AGS patient shows treatment with reverse transcriptase inhibitors (RTI) is beneficial. However, there is a gap in knowledge of whether ADAR1 mutations affect L1 RT function and impact downstream regulation of Alu retroelements and IFN in AGS. I am investigating if LINE-1 and Alu retroelements contribute to IFN mediated pathology in ADAR1-associated AGSand if RTI may be beneficial for ADAR1 patients. This research will address the critical the role of ADAR1 inthe regulation of retroelements and enhance our understanding of innate immunity and its implications in neurodegeneration.
