Kindy Lab
Research
Alzheimer’s disease (AD) affects more than 5 million people worldwide and is known as the most common form of dementia; the number of persons afflicted with dementia is also expected to grow further with the increase in the aging population worldwide. The ratio of diagnosis of AD increases to 1 in 3 after the age of 85 and results in death 3-9 years after the onset of symptoms. AD is associated with specific clinical and pathological features such as cognitive impairment and neuropsychiatric disturbances. AD is characterized by the aggregation of amyloid-beta (Abeta) peptide into neuritic plaques and hyperphosphorylated tau protein accumulating into neurofibrillary tangles (NFTs). Abeta is generated from the sequential cleavage of the amyloid-precursor protein (APP) resulting in the production of Abeta40 and Abeta42 peptides, which give rise to aggregated fibrils and plaques. Understanding the disease process is critical to the development of therapeutics for AD.
Stroke is one of the leading causes of disability and death in the United States (Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association, 2021). The outcome and infarction size after focal cerebral ischemia are determined by both “necrotic” cell death and by delayed neuronal cell loss in the border zone of ischemia (programmed cell death or apoptosis). Recent therapies have emerged to treat ischemic stroke; however, these treatments do not address neuroprotection, reduction of behavioral deficit or brain infarct volume once the neuronal cell death cycle has been triggered, and mostly deal with dissolving the blood clot. Past and current neuroprotective strategies have been successful in animal models but have failed significantly in clinical trials, as such there is a need for better therapeutics. Understanding the basic mechanisms that influence cell loss helps to design drugs that are targeted to reduce cell death associated with ischemic injury and improve functional outcome.
Selected Publications
Bruce, A.J., Boling, W., Kindy, M.S., Peschon, J., Kraemer, P.J., Carpenter, M.K., Holtsberg, F.W., Mattson, M.P. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. (1996) Nature Med. 2:788-794.
Mayeux R, Saunders AM, Shea S, Mirra S, Evans D, Roses AD, Hyman BT, Crain B, Tang MX, Phelps CH, for the Alzheimer’s Disease Centers Consortium on Apolipoprotein E and Alzheimer’s Disease. New Engl. J. Med. 1998;338:506-511.
Yan, S.D., Zhu, H., Zhu, A., Golabek, A., Wolozin, B., Roher, A., Yu, J., Chaney, M., Soto, C., Schmidt, A.M., Stern, D., Kindy, M.S. RAGE and amyloid fibrils: receptor-dependent signaling by beta-sheet fibrils mediates cellular stress in amyloidosis. Nature Medicine, 2000, 6:643-651.
El-Amouri, S.S, Zhu, H., Yu, J., Gage, F.H., Verma, I.M., Kindy. M.S. Neprilysin: an enzyme candidate to treat Alzheimer’s disease. Am J Pathol. 2008, 172:1342-54.
Yu, J., Gattoni-Celli, M., Zhu, H., Bhat, NR., Sambamurti, K., Gattoni-Celli, S., Kindy, M.S. Vitamin D3-Enriched Diet Correlates with a Decrease of Amyloid Plaques in the Brain of APP Transgenic Mice, J. Alz. Disease, 2011, 25:295-307.
Hook GR, Yu J, Sipes N, Pierschbacher M, Hook V, Kindy M. The Cysteine Protease Cathepsin B is an Important Drug Target and Cysteine Protease Inhibitors are Potential Therapeutics for Traumatic Brain Injury. J. Neurotrauma, 2014, 31(5):515-29.
Adams RJ, Ellis C, Magwood G, Kindy MS, Bonilha L, Lackland DT; WISSDOM Investigators. Commentary: Addressing Racial Disparities in Stroke: The Wide Spectrum Investigation of Stroke Outcome Disparities on Multiple Levels (WISSDOM). Ethn Dis. 2018 Feb 1;28(1):61-68.
Yu J, Zhu H, Taheri S, Mondy W, Bonilha L, Magwood GS, Lackland D, Adams RJ, Kindy MS. Serum amyloid A-mediated inflammasome activation in microglial cells. J Neurosci. 2019;39:9465-9476.
Yu J, Zhu H, Taheri S, Kirstein C, Kindy MS. Serum amyloid A-dependent inflammasome activation and acute injury in experimental stroke. Accepted to Communications Biology (Nature Research), 2021.