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William H. Frey II, Ph.D. Professor, Department of Neurology E-mail: alzheimr@umn.edu Alzheimer's Research Center

Research Interests:

We discovered a simple noninvasive way to deliver nerve growth factors and other therapeutic proteins to the brain. When administered as nose drops, these therapeutic proteins travel directly from the nose into the brain along the olfactory and trigeminal nerves. We and others have shown in animals that not only do these therapeutic proteins rapidly reach the brain by this method, but they are also able to dramatically reduce brain damage from neurologic disease such as stroke and Alzheimer's disease. When nose drops containing insulin-like growth factor-I were given to rats, even several hours after a stroke, brain damage was reduced by 65%, and the rats recovered most of their neurologic function in just a few days. Intranasal insulin-like growth factor-I should be similarly helpful in treating Alzheimer’s disease as well, since it can protect cholinergic neurons from damage by beta amyloid and increase acetylcholine. Researchers in Italy have used our intranasal nerve growth factor method to reverse Alzheimer's neurodegeneration in transgenic mouse models, others in California have demonstrated that intranasal nerve growth factors stimulate neurogenesis in adult animals resulting in new brain cells, while still others have used intranasal methotrexate to shrink brain tumors and intranasal leptin targeted to the hypothalamus to successfully treat obesity.

In collaboration with Suzanne Craft, we presented data at the Society for Neuroscience both in 2003 and 2004 demonstrating increased verbal memory in Alzheimer's patients with intranasal insulin that does not alter the blood level of insulin or glucose. [Also see Jan Born et al (2002) Natrue Neuroscience 5(6):514-516.] Finally, using the intranasal delivery method I discovered, Benedict et al. published a paper "Intranasal insulin improves memory in humans" in Psychoneuroendocrinology 29:1326-1334 (2004). This new method of targeting drugs to the brain can revolutionize the way we treat neurologic and psychiatric disorders while reducing systemic exposure and side effects of medication.

Additional information is available at the Alzheimer's Center web site www.alzheimersinfo.org. Students and staff with an interest in conducting research should contact Dr. Frey by phone at 651-254-2393 or e-mail at alzheimr@umn.edu.

Selected Publications:

Ma YP, Ma MM, Ge S, Guo RB, Zhang HJ, Frey WH 2nd, Xu GL, Liu XF. Intranasally delivered TGF-beta1 enters brain and regulates gene expressions of its receptors in rats. Brain Res Bull. 2007 Sep 28;74(4):271-7.

Wei G, Wang D, Lu H, Parmentier S, Wang Q, Panter SS, Frey WH 2nd, Ying W. Intranasal administration of a PARG inhibitor profoundly decreases ischemic brain injury. Front Biosci. 2007 Sep 1;12:4986-96.

Atamna H, Frey WH 2nd. Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer's disease. Mitochondrion. 2007 Sep;7(5):297-310.

Sajan FD, Martiniuk F, Marcus DL, Frey WH 2nd, Hite R, Bordayo EZ, Freedman ML. Apoptotic gene expression in Alzheimer's disease hippocampal tissue. Am J Alzheimers Dis Other Demen. 2007 Aug-Sep;22(4):319-28.

Pulliam L, Sun B, Rempel H, Martinez PM, Hoekman JD, Rao RJ, Frey WH 2nd, Hanson LR. Intranasal tat alters gene expression in the mouse brain. J Neuroimmune Pharmacol. 2007 Mar;2(1):87-92.

Hanson LR, Frey WH 2nd. Strategies for intranasal delivery of therapeutics for the prevention and treatment of neuroAIDS. J Neuroimmune Pharmacol. 2007 Mar;2(1):81-6.

Gerard HC, Dreses-Werringloer U, Wildt KS, Deka S, Oszust C, Balin BJ, Frey WH 2nd, Bordayo EZ, Whittum-Hudson JA, Hudson AP. Chlamydophila (Chlamydia) pneumoniae in the Alzheimer's brain. FEMS Immunol Med Microbiol. 2006 Dec;48(3):355-66.

Bordayo EZ, Fawcett JR, Lagalwar S, Svitak AL, Frey WH Jr. Inhibition of ligand binding to G protein-coupled receptors by arachidonic acid. J Mol Neurosci. 2005;27(2):185-94.

Reger MA, Watson GS, Frey WH 2nd, Baker LD, Cholerton B, Keeling ML, Belongia DA, Fishel MA, Plymate SR, Schellenberg GD, Cherrier MM, Craft S. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006 Mar;27(3):451-8.