Alzheimer and other tauopathies
Group leader: Prof. Karelle Leroy
Dr Leroy joined the ULB center for Diabetes research for her expertise on cellular and mouse modeling of the cerebral lesions found in Alzheimer’s disease, a dementia more frequently observed in individuals with diabetes.
Group leader: Prof. Karelle Leroy
Karelle Leroy obtained her PhD at the Université Libre de Bruxelles in 2003. During her PhD, she described for the first time the increased activity of Glycogen Synthase Kinase-3beta (GSK3beta) in the brain of people with Alzheimer’s disease. This kinase is responsible for abnormal tau phosphorylation, the first step leading to the development of neuronal lesions in this disease.
She is currently Professor at the ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Belgium. She has received several honors and awards.
Research Interests
Alzheimer’s disease is the most frequent neurodegenerative disease leading to dementia and cognitive deficits and represents a major health challenge for our aging societies as it has become the first cause of death in Belgium. There is no curative treatment for this disease. The etiopathogenesis of Alzheimer’s disease is relatively unknown as only 5% of Alzheimer cases are caused by familial mutations. This dementia is characterized by two neuropathological lesions, senile plaques composed of extracellular amyloid peptides and neurofibrillary tangles composed of abnormally phosphorylated and aggregated tau proteins forming paired helical filaments. Cognitive impairment strongly correlates with the abundance of neurofibrillary tangles. During disease development, tangle formation follows a neuroanatomical pathway suggesting that synaptically connected neurons could transmit tau pathology by the recruitment of normal tau by abnormal tau proteins in a prion-like mechanism. Several studies have shown that aggregated tau can recruit and seed murine or human mutant tau protein following their intracerebral injections. Even if the propagation of tau pathology could explain the formation of tangles in Alzheimer’s disease, the mechanism by which the abnormal tau protein can recruit normal tau remains unknown. Tau phosphorylation probably plays an important role as the internalization and secretion (two important steps in the propagation mechanism) of tau is increased when tau is phosphorylated by GSK3beta, a kinase shown to be closely associated to the first stages of tangles formation in the human disease.
Epidemiological studies show a clear association between type 2 diabetes and Alzheimer’s disease. Indeed, people with type 2 diabetes have a two-fold increased risk of developing Alzheimer. Moreover, type 2 diabetes in an elderly population with mild cognitive impairment influences the progression to dementia. As the activity of GSK3beta, a kinase involved in the insulin signaling pathway, is increased in Alzheimer’s disease, this kinase could be the possible link between these two pathologies.
The research of the Leroy lab is devoted to the understanding of the mechanisms of formation of neurofibrillary tangles by the analysis of human pathological brain tissue as well as cellular and animal models. Her team is undertaking preclinical therapeutic trials against Alzheimer and related tauopathies using nanomedicine and diabetes treatments.
Dr Leroy joined the ULB center for Diabetes research for her expertise on cellular and mouse modeling of the cerebral lesions found in Alzheimer’s disease, a dementia more frequently observed in individuals with diabetes.
Honours & Awards
2006 Travel fellowship award for the 10th international conference on Alzheimer’s disease and related disorders
2017 De Cooman prize
2020 Saucez-Van Poucke prize
2022 Simone and Pierre Clerdent prize
Selected Publications
Leroy K., Yilmaz Z., Brion JP. (2007) Increased level of active GSK-3ß in Alzheimer’s disease and accumulation in argyrophilic grains and in neurons at different stages of neurofibrillary degeneration, Neuropathology and Applied Neurobiology, 33 : 43-55.
Leroy K, Bretteville A, Schindowski K, Gillissen E, Authelet M, De Decker R, Yilmaz Z, Buée L, Brion JP (2007) Early axonopathy preceding neurofibrillary tangles in mutant Tau transgenic mice. The American Journal of Pathology, 171: 976-992.
Leroy K, Ando K, Héraud C, Yilmaz Z, Authelet M, Boeynaems JM, Buée L, De Decker R, Brion JP (2010) Lithium treatment arrests the development of neurofibrillary tangles in mutant tau transgenic mice with advanced neurofibrillary pathology. Journal of Alzheimer’s Disease, ; 19(2):705-19.
Leroy K., Ando K., Laporte V., Dedecker R., Suain V., Authelet M., Yilmaz Z., Octave J.N., Brion J.P. (2012) Lack of tau proteins rescues neuronal cell death and decreases amyloidognic processing of APP in APP/PS1 mice. AM. J. Pathol., , 181, 6, 1928- 1940.
Stygelbout V., Leroy K., Pouillon V., Ando K., D’Amico E., Yonghui J., Robert Luo H., Duyckaerts C., Erneux C., Schurmans S., Brion J-P., Inositol triphosphate 3-kinase B is increased in human Alzheimer brain and exacerbâtes mouse Alzheimer pathology. (2014) Brain, 137, 537-552.
Espuny Camacho I., Arranz M A., Fiers M., Snellinx A., Ando K., Munck S., Bonnefont J., Lambot L., Corthout N., Omodho L., Vanden-Eynden E., Radaelli E., Tesseur I., Wray S., Ebneth A., Hardy J., Leroy K., Brion JP., Vanderhaeghen P., De Strooper B., Hallmarks of Alzheimer disease in stem cell-derived human neurons transplanted into mouse brain. Neuron, 2017, 93: 1066- 1081.
Vanden Dries V., Stygelbout V., Pierrot N., Yilmaz Z., Suain V., De Decker R., Buée L., Octave JN., Brion JP., Leroy K., Amyloid precursor protein reduction enhances the formation of neurofibrillary tangles in a mutant tau transgenic mouse model. Neurobiology of aging, 2017, 55: 202-212.
Vergara C, Houben S, Suain V, Yilmaz Z, De Decker R, Vanden Dries V, Boom A, Mansour S, Leroy K, Ando K, Brion JP. Amyloid pathology enhances fibrillary tau seeding induced by Alzheimer PHF in vivo. Acta Neuropathol., 2019; 137 (3): 397-412
Ando K, De Decker R, Vergara C, Yilmaz Z, Mansour S, Suain V, Sleegers K, de Fisenne MA, Houben S, Potier MC, Duyckaerts C, Watanabe T, Buée L, Leroy K, Brion JP. Picalm reduction exacerbates tau pathology in a murine tauopathy model. Acta Neuropathol., 2020; 139 (4): 773-789.
Houben S, de Fisenne MA, Ando K, Vanden Dries V, Poncelet L, Yilmaz Z, Mansour S, De Decker R, Brion JP, Leroy K. Intraveinous injection of PHF-tau proteins from Alzheimer brain exacerbates neuroinflammation, amyloid beta, and tau pathologies in 5XFAD transgenic mice. Front. Mol. Neurosci.; 2020; 13: 106.
de Fisenne MA, Yilmaz Z, De Decker R, Suain V, Buée L, Ando K, Brion JP, Leroy K. Alzheimer PHF-tau aggregates do not spread tau pathology to the brain via the Retino-tectal projection after intraocular injection in mouse models. Neurobiol Dis. 2022 Sep 22:105875. doi: 10.1016/j.nbd.2022.105875.
