About the Nixon Laboratories

The Fate of Pathogenic Proteins in Neurodegenerative Diseases

In major neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, the abnormal accumulation of one or more polypeptides within or around neurons is central to pathogenesis. Our research focuses on two aspects of neurobiology that govern the fate of normal and pathogenic proteins: the regulation of proteolytic processing and the control of protein export into axons and synapses. We have identified dysfunction of the endosomal-lysosomal system, involving altered endocytosis and mistrafficking of proteases to endosomes, as the earliest known pathological response of neurons in Alzheimer’s disease. Our cell modeling studies show early endosomes to be major generators of the toxic ß-amyloid peptide and implicate dysfunction of endosomes in the mechanism of ß-amyloid accumulation in "sporadic" Alzheimer’s, the most common form of the disease. Genetic manipulations of proteolytic systems in mice are being used, together with cell culture models, to determine the consequences of endosomal-lysosomal and calpain system dysfunction on processing of Alzheimer-related proteins, receptor-mediated signal transduction, and neuronal cell death pathways.

To maintain neural circuitry, neurons transport a large proportion of their newly synthesized proteins into axons. The perikaryal accumulation of specific cytoskeletal proteins - a pathological hallmark of Alzheimer’s, ALS, and other neurologic diseases - is believed to arise in part from impaired axonal transport. A second interest of our research is to identify the molecular determinants of cytoskeletal protein transport and assembly in neurons. For example, we are defining the minimum structural requirements for neurofilament translocation by studying axonal transport and axon ultrastructure in mice after targeted deletion or mutagenesis of each of the three neurofilament subunit genes. Neurofilament transport is also regulated by sequential protein phosphorylation, triggered in part by signals from oligodendroglial cells. We have been determining the signaling pathways, phosphorylation sites, and functional implications of these post-translational modifications. Disease relevance is also being explored in several behavioral and psychiatric settings.



Recent Publications

Original Reports

Mathews PM, Guerra CB, Jiang Y, Grbovic OM, Kao BH, Schmidt SD, Dinakar R, Mercken M, Hille-Rehfeld A, Rohrer J, Mehta P, Cataldo AM, Nixon RA. Alzheimer’s disease-related overexpression of the cation-dependent mannose 6-phosphate receptor increases Aß secretion: Role for altered lysosomal hydrolase distribution in ß-amyloidogenesis. J Biol Chem 2002; 277:5299-5307.

Yang D-S, Tandon A, Chen F, Yu G, Yu H, Arawaka S, Hasegawa H, Duthie M, Schmidt, SD, Triprayer V, Ramabhadran TV, Nixon RA, Mathews PM, Gandy SE, Mount HTJ, St. George-Hyslop P, Fraser PE. Mature Glycosylation and Trafficking of Nicastrin Modulate Its Binding to Presenilins. J Biol Chem 2002; 277:28135-28142.

Mathews PM, Jiang Y, Schmidt SD, Grbovic OM , Mercken M, Nixon RA. Calpain activity regulates the cell surface distribution of amyloid precursor protein: inhibition of calpains enhances endosomal generation of ß-cleaved C-terminal APP fragments. J Biol Chem 2002; 277:36415-36424.

Di Rosa G, Odrijin T, Nixon RA, Arancio O. Calpain inhibitors: a treatment for Alzheimer's disease. J Molec Neurosci. 2002 Aug-Oct;19(1-2):135-41..

Rozmahel R, Mount HT, Chen F, Nguyen V, Huang J, Erdebil S, Liauw J, Yu G, Hasegawa H, Gu Y, Song YQ, Schmidt SD, Nixon RA, Mathews PM, Bergeron C, Fraser P, Westaway D, St. George-Hyslop P. Alleles at the nicastrin locus modify presenilin 1-deficiency phenotype. Proc Nat Acad Sci USA 2002; 99:14452-14457.

Adamec E, Mohan PS, Vonsattel JP, Nixon RA. Calpain activation in neurodegenerative diseases: confocal immunofluorescence study with antibodies specifically recognizing the active form of calpain 2. Acta Neuropathologica 2002; 104:92-104.

Adamec E, Murrell JR, Takao M, Hobbs W, Nixon RA, Ghetti B, Vonsattel JP. P301L tauopathy: confocal immunofluorescence study of perinuclear aggregation of the mutated protein. J Neurol Sci 2002; 200:85-93.

Rao, MV, Engle LJ, Mohan PS, Yuan A, Qiu D, Cataldo A, Hassinger L, Jacobsen S, Lee VM-Y, Andreadis A, Julien J-P, Bridgman PC, Nixon RA. Myosin Va binding to neurofilaments is essential for correct myosin Va distribution and transport and neurofilament density. J Cell Biol 2002; 159:279-289.

Rao MV, Garcia ML, Miyazaki Y, Gotow T, Yuan A, Mattina S, Ward CM, Calcutt NA, Uchiyama Y, Nixon RA, Cleveland DW. Gene replacement in mice reveals that the heavily phosphorylated tail of neurofilament heavy subunit does not affect axonal caliber or the transit of cargoes in slow axonal transport. J Cell Biol 2002; 158:681-693.

Noble W, Olm V, Takata K, Casey E, O M, Meyerson J, Gaynor K, LaFrancois J, Wang L, Kondo T, Davies P, Burns M, Veeranna , Nixon R, Dickson D, Matsuoka Y, Ahlijanian M, Lau L-F, Duff K.  Cdk5 is a key factor in tau aggregation and tangle formation. Neuron 2003; 38:555-565.

Battaglia F, Trinchese F, Liu S, Walter S, Nixon RA, Arancio O. Calpain inhibitors, a treatment for Alzheimer's disease: position paper. J Mol Neurosci. 2003 Jun;20(3):357-62.

Cataldo AM, Petanceska S, Peterhoff CM, Terio NB, Epstein CJ, Villar A, Carlson EJ, Staufenbiel M, and Nixon RA. Endosomal Abnormalities of Alzheimer’s Disease in a Trisomy 16 Mouse Model of Down Syndrome: Modulation by App Gene Dosage. J Neurosci. 2003; 23(17):6788-6792.

Grbovic OM, Mathews PM, Jiang Y, Schmidt SD, Dinaker R, Summers-Terio NB, Ceresa BP, Nixon RA, Cataldo AM. Rab5-stimulated up-regulation of the endocytic pathway increases intracellular ßCTF levels and A production. J Biol Chem. 2003; 278(33):31261-31268.

Yuan A, Rao MV, Kumar A, Julien J-P, Nixon RA. Neurofilament transport in vivo requires hetero-oligomer formation. J Neurosci. 2003; 23(28):9452-9458.

Phinney AL, Drisaldi B, Lugowski S, Schmidt SD, Coronado V, Liang Y, Horne P, Yang J, Sekoulidis J, Coomaraswamy J, Mathews PM, Nixon RA, Carlson GA, St George-Hyslop P, Westaway D. In vivo reduction of Aß by a mutant CuATPase7b transporter.  Proc. Natl. Acad. Sci. USA. 2003; 100:14193-14198.

Rao MV, Campbell J, Yuan A, Kumar A, Gotow T, Uchiyama Y, Nixon RA. The neurofilament middle molecular weight subunit carboxyl terminal tail domains are essential for the radial growth and cytoskeletal architecture of axons but not for regulating neurofilament transport rate. J Cell Biol 2003; 163:1021-1031.

Pawlik M, Sastre M, Calero M, Mathews PM, Schmidt SD, Nixon RA, Levy E.  Overexpression of human cystatin C in transgenic mice does not affect levels of endogenous brain amyloid ß peptide.  J Molecular Neuroscience, 2004; 22 (1-2): 13-8. 

Helpern JA, Lee S-P, Falangola MF, Dyakin VV, Bogart A, Estok K, Ardekani B, Duff K, Branch C, Wisniewski T, deLeon MJ, Wolf O, O’Shea J, Wegiel J, Nixon RA. Magnetic resonance imaging assessment of neuropathology in a transgenic mouse model of Alzheimer’s disease. Magn Reson Medicine, 2004; 51:794-798.

Laudon H, Mathews PM, Karlström H, Berman A, Farmery MR, Nixon RA, Winblad B, Gandy SE, Lendahl U, Lundkvist J, & Näslund J. Co-expressed presenilin 1 NTF and CTF form functional ß-secretase complexes in cells devoid of full-length protein. J Neurochem, 2004; 89:44-53.

Sadowski M, Pankiewicz J, Scholtzova H, Yong J, Quartermain D, Jensen CH, Duff K, Nixon RA, Gruen RJ, and Wisniewski T.  Amyloid-ß deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice.  JNEN, 2004; 63:418-428.

Yao J, Petanceska SS, Montine TJ, Holtzman DM, Schmidt SD, Parker SD, Callahan MJ, Lipinski WJ, Bisgaier CL, Turner BA, Nixon RA, Martins RN, Ouimet C, Smith JD, Ehrlich ME, Walker LC, Mathews PM, Gandy S.  Aging, gender, and apoE isotype modulate parallel trends in levels of Alzheimer’s amyloid ß peptides and F2-isoprostane biomarkers. J. Neurochemistry 2004;90:1011-1018.

Cataldo AM, Petanceska S, Terio NB, Peterhoff CM, Durham R, Mercken M, Mehta PD, Buxbaum J, Haroutunian V, Nixon RA. Aß localization in abnormal endosomes: association with earliest Aß elevation in AD and Down syndrome.  Neurobiol Aging 2004; 25:1263-1272.

Sastre M, Calero M, Pawlik M, Mathews PM, Kumar A, Danilov V, Schmidt SD, Nixon RA, Frangione B, and Levy E. Binding of cystatin C to Alzheimer’s amyloid-ß inhibits in vitro amyloid fibril formation.  Neurobiol Aging 2004 25:1033-1043.

Yu WH, Kumar A, Peterhoff C, Shapiro Kulkane L, Uchiyama Y, Lamb BT, Cuervo AM, Nixon RA. Autophagic vacuoles are enriched in APP-secretase activities: Implications for Aß peptide over-production and localization in Alzheimer’s disease. Int J Biochem Cell Biol 2004; 36:2531-2540.

Lee S-P, Falangola MF, Nixon RA, Duff K, Helpern JA. Visualization of ß-Amyloid Plaques in a Transgenic Mouse Model of Alzheimer's disease using MR microscopy without contrast reagents. Magn Reson Med  2004; 52:538-544.

Cataldo AM, Peterhoff CM, Schmidt SD , Terio N, Duff K, Beard M, Mathews PM, Nixon RA. Presenilin mutations in familial Alzheimer’s disease and transgenic mouse models accelerate neuronal lysosomal pathology. JNEN 2004; 63:821-830.

Veeranna , Kaji T, Boland B, Odrljin T, Mohan P, Basavarajappa B, Peterhoff C, Cataldo A, Rudnicki A, Li B-S, Pant HC, Hungund L, Arancio O, Nixon RA. Calpain mediates calcium-induced activation of the Erk1,2 MAPK pathway and cytoskeletal phosphorylation in neurons: relevance to Alzheimer’s disease. AM J Path 2004; 165:795-805.

Carter TL, Verdile Giuseppe, Groth D, Bogush A, Thomas S, Shen P, Fraser PE, Mathews P, Nixon RA, Ehrlich ME, Kwok JB, St. George-Hyslop P, Schofield P, Li Y, Yang A, Martins RN, Gandy S. Alzheimer amyloid precursor aspartyl proteinase activity in CHAPSO homogenates of Spodoptera frugiperda cells. Alzheimer Dis Assoc Disord 2004; 18:261-263.

Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study.  J Neuropathol Exp Neurol 2005; 64:113-122.

Falangola MF, Lee S-P, Nixon RA, Duff K, Helpern JA.  Histological co-localization of iron in Aß plaques of PS/APP Transgenic Mice. Neurochem Res 2005; 30:201-205.

Mastrangelo P, Mathews PM, Chishti MA, Schmidt SD, Gu Y, Yang J, Mazella MJ, Coomaraswamy J, Horne P, Strome B, Pelly H, Levesque G, Eberling C, Jiang Y, Nixon RA, Rozmahel R, Fraser PE, St George-Hyslop P, Carlson GA, Westaway D. Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases. Proc Nat Acad Sci USA 2005; 102:8972-8977.

de Grey AD, Alvarez PJ, Brady RO, Cuervo AM, Jerome WG, McCarty PL, Nixon RA, Rittmann BE, Sparrow JR.  Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age-related diseases.  Ageing Res Rev 2005 4:315-338.

Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Naslund J, Mathews PM, Cataldo AM, Nixon RA. Macroautophagy– a novel amyloid-ß (Aß) peptide-generating pathway activated in Alzheimer’s disease. J Cell Biology 2005; 171:87-98.

Yuan A, Nixon RA, Rao MV.  Deleting the phosphorylated tail domain of the neurofilament heavy subunit does not alter neurofilament transport rate in vivo. Neurosci Lett 2006; 393:264-268.

Yuan A, Rao MV, Chen Y, Kumar A, Veeranna , Peterson A, Julien J-P, Nixon RA. a-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS. JNeurosci (submitted).


Invited Reviews and Chapters

Nixon RA. Neural circuitry and signaling in dementia and Alzheimer’s disease. In: Brain Circuitry and Signaling in Psychiatry: Basic Science and Clinical Implications. Kaplan GB and Hammer RP, Jr. (eds.) American Psychiatric Publishing, Inc., WDC, 2002; 201-226.

Nixon RA. Cell and molecular neuropathology of Alzheimer’s disease. In: Neuropsycho- pharmacology: The Fifth Generation of Progress; Davis KL, Charney D, Coyle JT, and Nemeroff C (eds.) American College of Neuropsychopharmacology 2002; Lippincott Williams & Wilkins, Philadelphia, PA.

Tatton W, Chen D, Chalmers-Redman R, Wheeler L, Nixon R, Tatton N. Nixon RA. Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer’s disease: anti-apoptosis by alpha-2-adrenergic receptor activation. Survey of Ophthalmology 2003; 48: Supplement 1 p:S25-S37.

Rao MV and Nixon RA. Defective neurofilament transport in mouse models of amyotrophic lateral sclerosis: A review. Neurochem Res 2003; 28:1041-1047.

Matthews PM, Nixon RA. Setback for an Alzheimer’s disease vaccine: Lessons learned. Neurology 2003; 61(1):7/8. 

Nixon RA. The calpains in aging and aging-related diseases. Ageing  Research Reviews 2003; 2:407-418.

Nixon RA.  Niemann-Pick Type C disease and Alzheimer’s disease: The APP-endosome connection fattens up. American Journal of Pathology 2004; 164(3): 757-61.

Nixon RA. Endosome function and dysfunction in Alzheimer’s disease and other neurodegenerative diseases. Neurobiology of Aging 2005; 26:373-382.

Schmidt SD , Nixon RA, Mathews PM. ELISA method for measurement of amyloid-b levels. Methods in Molecular Biology: Amyloid Proteins, Methods and Protocols (Sigurdsson EM, editor), The Humana Press, Inc., Totowa, NJ 2005; 299:279-297. 

Schmidt SD , Jiang Y, Nixon RA, Mathews PM. Tissue processing prior to protein analysis and amyloid-b quantitation.  Methods in Molecular Biology: Amyloid Proteins, Methods and Protocols  (Sigurdsson EM, editor), The Humana Press, Inc., Totowa , NJ , 2005; 299:267-278.

Nixon RA and Cataldo AM. Lysosomal system pathways: Genes to neurodegeneration in Alzheimer’s disease. J Alzheimer’s Dis 2006; 7:1-13.

Nixon RA.  Autophagy in Neurodegenerative Disease:  Friend, Foe, or Turncoat? Trends in Neurosci 2006 (in press). 

Cataldo AM and Nixon RA. Neuronal trafficking in Alzheimer disease Niemann- Pick Type C disease. Neuro Biol Aging 2006; (in press).