Dr. Latha Diwakar

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About
People
Research
Academics

Senior Scientific Officer

Biosketch

Research

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Biosketch

I obtained my PhD in Neuroscience on ‘Gender related difference in pathogenesis of neurodegenerative disorders: role of mitochondrial dysfunction and protein thiol homeostasis’ at National Brain Research Centre, Manesar. I was Postdoctoral fellow in NIMHANS, Bengaluru, continued to work on animal model of ischemia and Identification of genetic risk factors in young stroke patients with high homocysteine to understand etio-pathogenesis of stroke. I worked as independent Research scientist at Vittal Mallya Scientific Research Foundation, Bengaluru on evaluating many potential drug molecules for their molecular mechanisms of chronic inflammatory diseases funded by DST and DBT. I joined as Research faculty in TATA grant at Centre for Neuroscience, Indian Institute of Science, started working on animal model of vascular dementia to know the commonality between vasoconstriction in brain and early AD in downstream pathways that drive to dementia.

Research

Dementia is a major public health issue in aging population with increasing life expectancy it becomes cause of concern in the society covering a spectrum of disorders including Alzheimer’s Disease (AD), Lewy body dementia and Vascular Dementia (VD). These are multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. Early intervention to delay progression of cognitive impairments are required to improve the deficits associated with dementia. MRI imaging shows these cerebrovascular lesions as white matter hyperintensities (WMH) adding significant burden to dementia over the age. However, there is no understanding how these small infarcts by themselves do not produce any functional disability till a certain burden is reached. What are the molecular drivers for these which would lead to cognitive dysfunction? To answer these questions there is need to develop an animal model replicating transient ischemic attack seen in patients that ultimately results in irreversible dementia.

We have developed an animal model of vascular dementia which can be manipulated to explore molecular underpinnings of disease pathogenesis simulating clinical scenario. Given such vascular insults in AD mice background could help us to understand the interplay between early cerebrovascular dysfunction with progressive synaptic dysfunction and formation of classic AD the plaques as well as neurofibrillary tangles. Such studies are important for deciphering the implication of vascular insult in patients with AD risk allele. We used endothelin-1 (ET-1) a 21 amino acid endogenous peptide, which acts through a G protein coupled receptor A or B expressed on endothelial cells bringing about vasoconstriction. To mimic a transient microinfarct rather than severe insult we injected ET-1 to C57 mice with stereotaxy into ventricles.

Single injection of ET-1 decreased CD31 expression, which is a marker for endothelial cells in ET-1 injected animals probably due to constriction in micro vessels brining about Blood Brain Barrier (BBB) dysfunction.

When we evaluated the consequence of reduced blood flow on learning and memory paradigm, ET-1 injected mice showed considerable decrease in spatial and associated memory. Activity dependent protein translation is important to maintain synaptic plasticity. Indeed, we found activity dependent protein translation was affected after of ET-1 injection indicating the cause for memory deficits.

We have demonstrated for first time the commonality between vasoconstriction in brain and early AD dysfunction in downstream pathways that drive the pathogenesis. However single vascular insult in mice is reversible giving us opportunity to study the components involved in regeneration of vessels offering potential therapeutic avenues for people with vascular dysfunction. Loss of BBB integrity results in increased vascular permeability and reduced cerebral blood flow is shown to be associated with cognitive decline in AD patients. Our animal model helps to define the molecular mechanisms during the pathogenesis of vascular insult. We need to investigate further underlying molecular mechanism and players involved in neuronal loss during repeated vascular insults.

People

Mayank

PhD Student

Publications

Diwakar L, Gowaikar R, Chithanathan K, Gnanabharathi B, Tomar DS, Ravindranath V. Endothelin-1 mediated vasoconstriction leads to memory impairment and synaptic dysfunction. Sci Rep. 2021 Mar 1;11(1):4868. doi: 10.1038/s41598-021-84258-x. PMID: 33649479; PMCID: PMC7921549.

Verma A, Ray A, Bapat D, Diwakar L, Kommaddi RP, Schneider BL, Hirsch EC, and Ravindranath V. (2020), Glutaredoxin 1 Downregulation in the Substantia Nigra Leads to Dopaminergic Degeneration in Mice. Movement Disorders. doi:10.1002/(ISSN)1531-8257. 2020.

Ahmad F, Das D, Kommaddi RP, Diwakar L, Gowaikar R, Rupanagudi KV, Bennett DA, Ravindranath V. Isoform-specific hyperactivation of calpain-2 occurs presymptomatically at the synapse in Alzheimer’s disease mice and correlates with memory deficits in human subjects. Sci Rep. 2018 Sep 3; 8(1):13119.

S Shenvi, KR Kiran, K Kumar, Diwakar L, GC Reddy. Synthesis and biological evaluation of boswellic acid-NSAID hybrid molecules as anti-inflammatory and anti-arthritic agents. European journal of medicinal chemistry 98, 170-178. 2015.

Samaga L, KK, Rao GV, Reddy GC, Kush AK, Diwakar L. Synthetic racemates of abyssinone I and II induces apoptosis through mitochondrial pathway in human cervix carcinoma cells. Bioorganic Chemistry 56: 54-61. 2014.

Shenvi S, Kumar K, Hatti KS, Rijesh K, Diwakar L, Reddy G.C. Synthesis, anticancer and antioxidant activities of 2,4,5-trimethoxy chalcones and analogues from asaronaldehyde: Sturcture-activity relationship. European Journal of Medicinal Chemistry 62 435-442. 2013.

Diwakar L, Rudresh Kumar KJ, Bachnalkar A, Ravindranath V, Christopher R, Nagaraja D. The influence of MTR A2756G polymorphism on plasma homocysteine in young south Indians. ClinChimActa. 395, 172-174. 2008.

Diwakar L, Ravindranath V. Inhibition of cystathionine-gamma-lyase leads to loss of glutathione and aggravation of mitochondrial dysfunction mediated by excitatory amino acid in the CNS. Neurochem Int. 50, 418-426. 2007.

Diwakar L, Kenchappa RS, Annepu J, Saeed U, Sujanitha R, Ravindranath V, Down-regulation of glutaredoxin by estrogen receptor antagonist renders female mice susceptible to excitatory amino acid mediated complex I inhibition in CNS. Brain Res.1125(1):176-184. 2006.

Diwakar L, Kenchappa RS, Annepu J, Saeed U, Sujanitha R, Ravindranath V, Down-regulation of glutaredoxin by estrogen receptor antagonist renders female mice susceptible to excitatory amino acid mediated complex I inhibition in CNS. Brain Res.1125(1):176-184. 2006.

Kenchappa RS, Diwakar L, Annepu J, Ravindranath V. Estrogen and neuroprotection: higher constitutive expression of glutaredoxin in female mice offers protection against MPTP-mediated neurodegeneration. FASEB J. 18:1102-1114. (Co-first author). 2004.

Devi L, Diwakar L, Raju TR, Kutty BM. Selective neurodegeneration of hippocampus and entorhinal cortex correlates with spatial learning impairments in rats with bilateral ibotenate lesions of ventral subiculum. Brain Res. 960:9-15. 2003.

Kenchappa RS, Diwakar L, Boyd MR, Ravindranath V. Thioltransferase (glutaredoxin) mediates recovery of motor neurons from excitotoxic mitochondrial injury. J Neurosci. 22:8402-8410. 2002.

Opportunities & Resources

Opportunities: Research Fellows

The mandate of CBR is to conduct impactful research on normal and pathological aging of the brain to identify risk factors and protective factors for neurodegeneration

CBR spearheads diverse research projects on Alzheimer’s disease, vascular dementia, and other neurodegenerative disorders.

CBR is inviting applications from highly motivated candidates for ‘Research Fellow’ positions to work on projects involving molecular biology techniques, animal experiments, cell culture, and microscopy. The positions offer excellent opportunities to engage in cutting-edge neuroscience research.

Qualification and Skills

Essential: MSc/MTech or equivalent in Life Sciences (e.g., Neuroscience, Biotechnology, Molecular Biology, Zoology, Biochemistry, Chemistry)

Desirable: Prior research experience in animal handling, cell culture, and molecular biology techniques is preferred.

Selection

Interested candidates should send their CV and a cover letter (1 page) together as a single file (.pdf) to this mail ID (with the subject line ‘Application for Research Fellow Position’) on or before 06 September 2024. The CV must include contact details of at least 2 referees who can provide feedback on the candidate’s abilities. Selection will be based on academic merit, technical proficiency, and expertise in the subject area. CBR reserves the right to not fill the vacancy in case a suitable candidate is not found.

Contact

For more information on CBR’s research projects and other initiatives, please visit https://cbr-iisc.ac.in. Any queries may be addressed here.

Contact

Centre for Brain Research
Indian Institute of Science Campus
CV Raman Avenue
Bangalore 560012, India.
+91 80 2293 3588

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