Repair Mechanisms in the Brain
The 100,000 Gbyte hard-drive we call our brain is a challenge to study, also making it a challenge to find therapeutic treatments against the numerous diseases that disrupt memory encoding and other brain functions. In my lab, slices of brain tissue are kept alive to examine neuronal connections responsible for memory processing as well as cellular maintenance pathways, and to study their vulnerability to pathogenesis. While the brain’s incredible density of synaptic connections allows for extraordinary memory capacity, the abundant synapses are also vulnerable to pathogenic over-activation. Such excitotoxic brain damage can occur in many disease states including stroke, traumatic injury, and seizure events. We are studying the pharmacological enhancement of endogenous compensatory pathways to offset the damage, and we found that positive modulation of internal repair mechanisms protects against the damaging effects of seizures and stroke-type excitotoxic insults. Our other focus is to study age-related neurodegenerative disorders. Every 72 seconds someone in the U.S. develops Alzheimer’s disease (AD) due to suspected imbalances between protein production and protein clearance. Reducing Alzheimer-type protein accumulation is essential for slowing the progression of the disease. Lysosomes and their degradative enzymes (e.g. cathepsins) are known to respond to AD, likely in an attempt to offset the abnormal protein accumulations that cause a distinct cascade of synaptopathogenesis. To treat the impaired clearance of particular protein species, we discovered a new class of drugs that act as positive modulators of the lysosomal response, resulting in the up-regulation of cathepsins as well as neuroprotection in cultured brain slices and in mouse models of AD.
Members of the William C. Friday Laboratory
Bahr BA (2009) Lysosomal modulatory drugs for a broad strategy against protein accumulation disorders. Current Alzheimer Res 6:438-445.
Hwang J, Adamson C, Butler D, Janero DR, Makriyannis A, and Bahr BA (2010) Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: A neuroprotective therapeutic modality. Life Sciences (special issue: Emerging Technologies in Drug Development) 86:615-623.
Naidoo V, Nikas SP, Karanian DA, Hwang J, Zhao J, Wood JT, Alapafuja SO, Vadivel SK, Butler D, Makriyannis A, and Bahr BA (2011) A new generation fatty acid amide hydrolase inhibitor protects against kainate-induced excitotoxicity. J Mol Neuroscience 43:493-502.
Butler D, Hwang J, Estick C, Nishiyama A, Kumar SS, Baveghems C, Young-Oxendine HB, Wisniewski ML, Charalambides A, and Bahr BA (2011) Protective effects of positive lysosomal modulation in Alzheimer’s disease transgenic mouse models. PLoS One 6: e20501 (pp 1-16).
Wisniewski ML, Hwang J, and Bahr BA (2011) Submicromolar Aβ42 reduces hippocampal glutamate receptors and presynaptic markers in an aggregation-dependent manner. Biochim Biophys Acta (Mol. Basis of Disease) 1812:1664-1674.
Zheng X, Gessel MM, Wisniewski ML, Viswanathan K, Wright DL, Bahr BA, and Bowers MT (2012) Z-Phe-Ala-diazomethylketone (PADK) disrupts and remodels the early oligomer states of the Alzheimer’s disease Aβ42 protein. J Biol Chem, in press (Jan. Epub).
Naidoo V, Karanian DA, Vadivel SK, Locklear JR, Wood JT, Nasr M, Quizon PMP, Graves EE, Shukla V, Makriyannis A, and Bahr BA (2012) Equipotent inhibition of fatty acid amide hydrolase and monoacylglycerol lipase – dual targets of the endocannabinoid system to protect against seizure pathology. Neurotherapeutics, in press (Jan. Epub).
Bahr BA, Wisniewski ML, and Butler D (2012) Positive lysosomal modulation as a unique strategy to treat age-related protein accumulation diseases. Rejuvenation Res: in press.
Updated: Thursday, March 22, 2012
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