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The primary focus of my lab is to investigate the relationship between APOE genotype and late onset Alzheimer’s disease (AD). The single most common and influential gene in AD is the APOE gene. The APOE gene is polymorphic; encoding three different alleles designated APOE2, E3 or E4. APOE4 carriers have the highest risk for AD while APOE3 carriers have an essentially neutral risk and APOE2 carriers may be protected against AD. The APOE4 gene is also linked to increased risk for atherosclerosis, cerebral amyloid angiopathy, peripheral neuropathy, multiple sclerosis, stroke and type II diabetes; as well as an increased susceptibility to HIV and Chlamydia infections, head injury and cognitive decline following coronary bypass surgery. The fact that 28% of the US population are carriers of the APOE4 gene, underscores the need for a better understanding of APOE’s relationship to disease. The major challenge facing researchers today is determining why some APOE4 carriers succumb to disease while others do not. Genetic modifiers and environmental risk factors likely explain different individual outcomes. The primary environmental risk factors are thought to be; a Westernized diet, low physical activity, chronic stress, poor sleep habits, andro/menopause and most importantly, age.
We are currently working to test novel drug formulations that specifically target putative apoE dependent mechanisms involved in neurodegeneration. Our initial screens involve neuronal-glial cell culture models that eventually will lead to testing in animals. We currently use the best available animal model of apoE-linked AD, the human apoE targeted replacement (TR) or “knock in” mice. I created three lines of human apoE TR mice, each expressing one the three human apoE isoforms and have since made multiple crosses to other AD related genes (e.g. APP, PS1 and tau). I have given the apoE TR mice and made the crosses available to over 70 labs worldwide.
We are also working to build a better model of late onset AD by combining the apoE TR mice with non-mutated human APP and tau KI mice. We think this is important because over 98% of all AD cases contain no mutations in the APP or tau genes. Our hope is to better understand the true etiology and progression of late onset AD. If successful this new model should aid in both novel target identification and new drug testing to produce therapeutics with greater efficacy in treating AD.
We are currently working to test novel drug formulations that specifically target putative apoE dependent mechanisms involved in neurodegeneration. Our initial screens involve neuronal-glial cell culture models that eventually will lead to testing in animals. We currently use the best available animal model of apoE-linked AD, the human apoE targeted replacement (TR) or “knock in” mice. I created three lines of human apoE TR mice, each expressing one the three human apoE isoforms and have since made multiple crosses to other AD related genes (e.g. APP, PS1 and tau). I have given the apoE TR mice and made the crosses available to over 70 labs worldwide.
We are also working to build a better model of late onset AD by combining the apoE TR mice with non-mutated human APP and tau KI mice. We think this is important because over 98% of all AD cases contain no mutations in the APP or tau genes. Our hope is to better understand the true etiology and progression of late onset AD. If successful this new model should aid in both novel target identification and new drug testing to produce therapeutics with greater efficacy in treating AD.
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NEUROCHEMISTRY INTERNATIONAL (2024): 105680-105680
FREE RADICAL BIOLOGY AND MEDICINE (2024): 191-198
Brendan Miller,Su-Jeong Kim,Kevin Cao,Hemal H. Mehta,Neehar Thumaty,Hiroshi Kumagai, Tomomitsu Iida,Cassandra Mcgill,Christian J. Pike, Kamila Nurmakova,Zachary A. Levine,Patrick M. Sullivan,
AGING CELLpp.e14153-e14153, (2024)
FISH AND FISHERIESno. 1 (2024): 38-59
Mark A. Colijn,Prescilla Carrion,Guillaume Poirier-Morency,Sanja Rogic,Ivan Torres,Mahesh Menon,Michelle Lisonek,Courtney Cook, Ashley DeGraaf, Subramanya Ponnachana Thammaiah, Harish Neelakant,Veerle Willaeys,
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY (2024): 110888-110888
Experimental neurology (2023): 114356-114356
Journal of medicinal chemistry (2023)
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