Understanding the molecular basis of neurodegenerative and neuropsychiatric diseases.
We are exploring what goes wrong in the brains of patients with diseases such as Alzheimer's, Parkinson's, and schizophrenia, and our aim is to test therapeutic approaches that may be beneficial for the treatment, or prevention of these diseases. Our main focus is on Alzheimer's disease and the contribution of tangles to disease, especially the role of aberrant phosphorylation of specific proteins such as tau, in disease progression. We also have new projects looking at pathogenic mechanisms in Parkinson's disease (especially the role of autophagy) and the identification and investigation of a new pathway implicated in schizophrenia. In addition, we are examining the impact of diabetes on tangle formation in Alzheimer's disease. We are using several transgenic mouse models which allow us to examine, and modulate, pathways of interest. We have examined the impact of pathways involved in, for example, aberrant phosphorylation of tau protein in tangles both genetically (through crosses to other transgenic mice, or through viral induction of genes) and also pharmacologically using drugs. In the case of our work on Lithium, data generated is of direct interest to clinicians looking for non-proprietary treatments for patients, and to support clinical trials. This sort of translational neuroscience has high clinical relevance, as it covers a wide range of techniques and approaches, and it is applicable to a number of different diseases.
1. Area-Gomez E, de Groof AJ, Boldogh I, Bird TD, Gibson GE, Koehler CM, Yu WH, Duff KE
, Yaffe MP, Pon LA, Schon EA. Presenilins Are Enriched in Endoplasmic Reticulum Membranes Associated with Mitochondria. Am J Pathol. 2009 Oct 15. [Epub ahead of print]
2. Yu WH, Dorado B, Figueroa HY, Wang L, Planel E, Cookson MR, Clark LN, Duff KE
. Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric alpha-synuclein. Am J Pathol. 2009 Aug;175(2):736-47. Epub 2009 Jul 23.
3. Congdon EE, Figueroa YH, Wang L, Toneva G, Chang E, Kuret J, Conrad C, Duff KE
. Inhibition of tau polymerization with a cyanine dye in two distinct model systems. J Biol Chem. 2009 Jul 31;284(31):20830-9. Epub 2009 May 28.
4. Chang E, Congdon EE, Honson NS, Duff KE
, Kuret J. Structure-activity relationship of cyanine tau aggregation inhibitors. J Med Chem. 2009 Jun 11;52(11):3539-47.
5. Planel E, Bretteville A, Liu L, Virag L, Du AL, Yu WH, Dickson DW, Whittington RA, Duff KE
. Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia. FASEB J. 2009 Aug;23(8):2595-604. Epub 2009 Mar 11.
6. Choi JJ, Wang S, Brown TR, Small SA, Duff KE
, Konofagou EE. Noninvasive and transient blood-brain barrier opening in the hippocampus of Alzheimer's double transgenic mice using focused ultrasound. Ultrason Imaging. 2008 Jul;30(3):189-200.
7. Planel E, Krishnamurthy P, Miyasaka T, Liu L, Herman M, Kumar A, Bretteville A, Figueroa HY, Yu WH, Whittington RA, Davies P, Takashima A, Nixon RA, Duff KE
.Anesthesia-induced hyperphosphorylation detaches 3-repeat tau from microtubules without affecting their stability in vivo. J Neurosci. 2008 Nov 26;28(48):12798-807.
8. Congdon EE, Duff KE
. Is tau aggregation toxic or protective? J Alzheimers Dis. 2008 Aug;14(4):453-7. Review.
9. Hirata-Fukae C, Li HF, Hoe HS, Gray AJ, Minami SS, Hamada K, Niikura T, Hua F, Tsukagoshi-Nagai H, Horikoshi-Sakuraba Y, Mughal M, Rebeck GW, LaFerla FM, Mattson MP, Iwata N, Saido TC, Klein WL, Duff KE
, Aisen PS, Matsuoka Y.
Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res. 2008 Jun 24;1216:92-103. Epub 2008 Apr 10.
10. Wen Y, Planel E, Herman M, Figueroa HY, Wang L, Liu L, Lau LF, Yu WH, Duff KE
. Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. J Neurosci. 2008 Mar 5;28(10):2624-32.