In 2010 - 5 million,       

 by 2050 > 13 million

...people in the U.S. with Alzheimer's disease. It is an exponentially growing problem. No effective treatments, yet total funding for AD is $500M while funding for cancer is $6B and AIDS is $3B.

 

 

 

Recent ALSP Scientific Presentations

 

Presentations on December 1-4 at Cold Spring Harbor Laboratory 2010 Meeting on NEURODEGENERATIVE DISEASES: BIOLOGY & THERAPEUTICS

 

>Pharmacogenetic features of inhibitors to cathepsin B that improve memory deficit and reduce beta-amyloid related to Alzheimer's Disease

by Hook, V. Y. H. and Kindy, M. and Funkelstein, L. and Hook, G.

 

>Cathepsin B inhibition reduces brain beta-amyloid peptides while increasing brain BACE1 activity in animal models expressing APP with the normal beta-secretase site sequence

by Hook, G. and Hook, V. Y. H. and Kindy, M.

 

>Roles of BACE-1 and Cathepsin B in the generation of Abeta peptide in Alzheimer's Disease

by Hook, V. Y. H. and Hook, G. and Kindy, M. et al.

 

 

Presentations on November 13-17 at NEUROSCIENCE 2010 in San Diego

 

>Roles of BACE-1 and Cathepsin B in the generation of Abeta peptide in Alzheimer's Disease

by Kindy, M. S. and Hook, V. Y. H. and Hook, G. et al.

 

>Oral administration of cathepsin B inhibitor reduces brain Abeta in guinea pigs

by Hook, G. and Kindy, M. 

 

 

ALSP Publications

 

>Cysteine Cathepsins in the Secretory vesicle produce active peptides: Cathepsin L generates peptide neurotransmitters and cathepsin B produces beta-amyloid of Alzheimer's disease

Biochimica et Biophysica acta. (2011 Sep 8) [Epub ahead of print]

by Hook, V. Y. H. and Hook, G. and Kindy, M. et al.

Read...

 

>The Cysteine Protease Inhibitor, E64d, Reduces Brain Amyloid-beta and Improves Memory Deficits in Alzheimer's Disease Animal Models by Inhibiting Cathepsin B, but not BACE1, beta-secretase Activity

Journal of Alzheimer's Disease, (2011) 26: 387-408

by Hook, V. Y. H. and Hook, G. and Kindy, M.

Read...

 

>Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce beta-amyloid related to Alzheimer's Disease

Biological Chemistry, (2010) 391: 861-872

by Hook, V. Y. H. and Hook, G. and Kindy, M.

Read...

 

> Genetic cathepsin B deficiency reduces beta-amyloid in transgenic mice expressing human wild-type amyloid precursor protein

Biochemical and Biophysical Research Communications, (2009) 386: 284-288

by Hook, V. Y. H. and Hook. G. et al.

Read...

 

> Inhibitors of Cathepsin B improve Memory and Reduce beta-amyloid in Transgenic Alzheimer Disease Mice Expressing the Wild-type, but not the Swedish Mutant, beta-secretase Site of the Amyloid Precursor Protein

The Journal of Biological Chemistry, (2008) 283: 7745-7753

by Hook, V. Y. H. and Hook, G. et al.

Read...

 

> Alternative Pathways for Production of beta-amyloid Peptides of Alzheimer's Disease

Biological Chemistry, (2008) 389: 993-1006

by Hook, V. Y. H and Hook, G. et al.

Read...

 

> Cysteine Protease Inhibitors Effectively Reduce in Vivo Levels of brain beta-amyloid Related to Alzheimer's Disease

Biological Chemistry, (2007) 388: 247-252

by Hook, V. et al.

Read...

 

> Inhibition of cathepsin B reduces beta-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate beta-secretase of Alzheimer's Disease

Biological Chemistry, (2005) 386: 931-940

by Hook, V. et al.

Read...

 

> Cysteine Proteases are the Major beta-secretase in the Regulated Secretory Pathway that Provides Most of the beta-amyloid in Alzheimer's Disease: Role of BACE 1 in the Constitutive Secretory Pathway

Journal of Neuroscience Research, (2003) 74: 393-405

by Hook, V. Y. H. and Reisine, T D.

Read...

 

> Beta-amyloid peptide in regulated secretory vesicles of chromaffin cells: Evidence for Multiple Cysteine Proteolytic Activities in Distinct Pathways for beta-secretase activity in chromaffin vesicles

Journal of Neurochemistry, (2002) 82: 237-256

by Hook, V. et al.

Read...


Relevant Bibliography


Alzheimer’s Disease

Beck M, Bigl V, Rossner S. Guinea pigs as a nontransgenic model for APP processing in vitro and in vivo. Neurochem Res 28:637-644.2003.

 

Billen LP, Shamas-Din A, Andrews DW. Bid: a Bax-like BH3 protein. Oncogene 27 Suppl 1:S93-104.2008.

 

Cataldo AM, Barnett JL, Pieroni C, Nixon RA. Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. J Neurosci 17:6142-6151.1997.

 

Ditaranto K, Tekirian TL, Yang AJ. Lysosomal membrane damage in soluble Abeta-mediated cell death in Alzheimer's disease. Neurobiol Dis 8:19-31.2001.

 

Friedlander RM. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 348:1365-1375.2003.

 

Furukawa K, Sopher BL, Rydel RE, Begley JG, Pham DG, Martin GM, Fox M, Mattson MP. Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J Neurochem 67:1882-1896.1996.

 

Huang Y, Wang KK. The calpain family and human disease. Trends Mol Med 7:355-362.2001.

 

Miyahara T, Shimojo S, Toyohara K, Imai T, Miyajima M, Honda H, Kamegai M, Ohzeki M, Kokatsu J. Clinical Phase I trial of thiol protease inhibitor  (Report 2):  safety and pharmacokinetics in continuous administration. Rinsho Yakuri 16:537-546.1985a.

 

Nixon RA, Cataldo AM, Mathews PM. The endosomal-lysosomal system of neurons in Alzheimer's disease pathogenesis: a review. Neurochem Res 25:1161-1172.2000.

 

Oyama F, Murakami N, Ihara Y. Chloroquine myopathy suggests that tau is degraded in lysosomes: implication for the formation of paired helical filaments in Alzheimer's disease. Neurosci Res 31:1-8.1998.

 

Perlmutter LS, Siman R, Gall C, Seubert P, Baudry M, Lynch G. The ultrastructural localization of calcium-activated protease "calpain" in rat brain. Synapse 2:79-88.1988.

 

Roberts GW, Gentleman SM, Lynch A, Murray L, Landon M, Graham DI. Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease. J Neurol Neurosurg Psychiatry 57:419-425.1994.

 

Saito K, Elce JS, Hamos JE, Nixon RA. Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. Proc Natl Acad Sci U S A 90:2628-2632.1993.

 

Stoka V, Turk B, Turk V. Lysosomal cysteine proteases: structural features and their role in apoptosis. IUBMB Life 57:347-353.2005.

 

Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK. Co-occurrence of Alzheimer's disease ss-amyloid and tau pathologies at synapses. Neurobiol Aging 31:1145-1152.2010.

 

Trinchese F, Fa M, Liu S, Zhang H, Hidalgo A, Schmidt SD, Yamaguchi H, Yoshii N, Mathews PM, Nixon RA, Arancio O. Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease. J Clin Invest 118:2796-2807.2008.

 

Wang KK. Calpain and caspase: can you tell the difference? Trends Neurosci 23:20-26.2000.

 

Yeung BH, Huang DC, Sinicrope FA. PS-341 (bortezomib) induces lysosomal cathepsin B release and a caspase-2-dependent mitochondrial permeabilization and apoptosis in human pancreatic cancer cells. J Biol Chem 281:11923-11932.2006.

 

Zhang L, Sheng R, Qin Z. The lysosome and neurodegenerative diseases. Acta Biochim Biophys Sin (Shanghai) 41:437-445.2009.

 

Traumatic Brain Injury

Beauchamp K, Mutlak H, Smith WR, Shohami E, Stahel PF. Pharmacology of traumatic brain injury: where is the "golden bullet"? Mol Med 14:731-740.2008.

 

Clark RS, Kochanek PM, Chen M, Watkins SC, Marion DW, Chen J, Hamilton RL, Loeffert JE, Graham SH. Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. Faseb J 13:813-821.1999.

 

DoD. Traumatic Brain Injury Care in the Department of Defense. http://wwwdcoehealthmil/Content/Navigation/Documents/Traumatic%20Brain%20Injury%20Care%20in%20the%20Department%20of%20Defensepdf. September 2009.

 

Laino C. TBI in Vets May Raise Dementia Risk, According to New Report. Neurology Today 11:1, 34-35.2011.

 

Luo CL, Chen XP, Yang R, Sun YX, Li QQ, Bao HJ, Cao QQ, Ni H, Qin ZH, Tao LY. Cathepsin B contributes to traumatic brain injury-induced cell death through a mitochondria-mediated apoptotic pathway. J Neurosci Res 88:2847-2858.2010.

 

McAllister TW. Neurobiological consequences of traumatic brain injury. Dialogues Clin Neurosci 13:287-300.2011. Ray SK, Dixon CE, Banik NL. Molecular mechanisms in the pathogenesis of traumatic brain injury. Histol Histopathol 17:1137-1152.2002.

 

Terrio H, Brenner LA, Ivins BJ, Cho JM, Helmick K, Schwab K, Scally K, Bretthauer R, Warden D. Traumatic brain injury screening: preliminary findings in a US Army Brigade Combat Team. J Head Trauma Rehabil 24:14-23.2009.

 

Uryu K, Laurer H, McIntosh T, Pratico D, Martinez D, Leight S, Lee VM, Trojanowski JQ. Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci 22:446-454.2002.

 

Werner C, Engelhard K. Pathophysiology of traumatic brain injury. Br J Anaesth 99:4-9.2007.

 

Zheng Z, Sabirzhanov B, Keifer J. Oligomeric amyloid-beta inhibits the proteolytic conversion of the Brain-derived Neurotrophic Factor (BDNF), AMPA receptor trafficking, and classical conditioning. J Biol Chem 285: 34708-34717.

 

Huntington’s Disease

 

Kim YJ, Yi Y, Sapp E, Wang Y, Cuiffo B, Kegel K, Qin Z-H, Aronin N, DiFiglia M. Caspase 3-cleaved N-  terminal fragments of wild type and mutant huntingtin are present in normal and Huntington’s disease brains, associate with membranes, and undergo calpain-dependent proteolysis.  PNAS 98 (22): 12784-12789. 2001.

 

Kim YJ, Sapp E, Cuiffo BG, Sobin L, Yoder J, Kegel KB, Qin ZH, Detloff P, Aronin N, DiFiglia M. Lysosomal proteases are involved in generation of N-terminal huntingtin fragments. Neurobiol Dis 22:346-356.2006.

 

Ischemia

 

Tsubokawa T, Solaroglu I, Yatsushige H, Cahill J, Yata K, Zhang JH. Cathepsin and calpain inhibitor E64d attenuates matrix metalloproteinase-9 activity after focal cerebral ischemia in rats. Stroke 37:1888-1894.2006a.

 

Tsubokawa T, Yamaguchi-Okada M, Calvert JW, Solaroglu I, Shimamura N, Yata K, Zhang JH. Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats. J Neurosci Res 84:832-840.2006b.