Calpain inhibitors: a treatment for Alzheimer's disease.
Activation of the calpain system might contribute to the impairment of synaptic transmission in Alzheimer's disease (AD) (Liu et al., 1999; Rapoport, 1999; Selkoe, 1994). Calpains regulate the function of many proteins by limited proteolysis and initiate the complete degradation of other proteins. In particular, they modulate processes that govern the function and metabolism of proteins key to the pathogenesis of AD, including tau and amyloid precursor protein (APP). (Xie and Johnson, 1998; Wang, 2000). We have found that overexpression of APP(K670M:N671L) and PS1(M146L) proteins in hippocampal cultures derived from transgenic mice causes an increase in the frequency of spontaneous release of neurotransmitter. We have also found that calpain immunoreactive clusters are co-localized with immunoreactivity for the vesicle-associated presynaptic marker, synaptophysin. Moreover, application of calpain inhibitor reduces the frequency of spontaneous release of neurotransmitter. Therefore, we have hypothesized that calpains might contribute to the increase in transmitter release. Based on this hypothesis, we propose to test whether it is possible to restore normal synaptic transmission between cells derived from the transgenic model of AD by using calpain inhibitors. The transgenic mouse model also shows spatial learning impairment, a phenomenon that is thought to be associated with plastic changes at synaptic level. Therefore, we will also test whether we can rescue the learning impairment through a treatment with calpain inhibitors.
Di Rosa
Gabriella
G
Nathan Kline Institute, NYU School of Medicine, Orangeburg, NY 10962, USA.
Odrijin
Tatjana
T
Nixon
Ralph A
RA
Arancio
Ottavio
O
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D002154:Calpain / Q000378:metabolism*; D018929:Cell Culture Techniques; D004594:Electrophysiology; D005838:Genotype; D006023:Glycoproteins / Q000627:therapeutic use*; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D007858:Learning / Q000187:drug effects; D007976:Leupeptins / Q000627:therapeutic use; D051379:Mice; D009473:Neuronal Plasticity; D009435:Synaptic Transmission / Q000187:drug effects; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
D016564:Amyloid beta-Protein Precursor; D006023:Glycoproteins; D007976:Leupeptins; D016708:Synaptophysin; C039304:calpain inhibitors; D002154:Calpain; C032854:leupeptin