Agonist Selection

Importantly, in cor tical neurons from BACE null embr yos, there is no cleavage at the and sites of A, and the secretion of A peptides is abolished even in the presence of elevated level of exogenous APP.Moreover, A pept ides are not produced in Cefadroxil brains of BACE null mice.Although behavioral studies on BACE null mice are necessary to determine the effect of the absence of BACE, results thus far indicate that BACE is an excellent therapeutic target for drug development for AD.These mouse models have revealed that neurons are the major source for A production in the brain.Because BACE is the principal secretase in neurons, and BACE may serve to limit the secretion of A peptides, we hypothesized that the relative levels of BACE and BACE activities are major determinants of A amyloidosis.Seemingly inconsistent with this hypothesis is a study show ing high levels of BACE mRNA expression in the pancreas.Taken together with the observations that pancreas possesses low levels of BACE protein and activity, these results are consistent with the view that a high ratio of BACE to BACE activity leads to selective vulnerability of neurons to A amyloidosis, whereas pancreatic cells are spared.Although they do not model the full phenotype of AD, these mutant transgenic mice represent excellent models of A amyloidois and are highly suitable for identification of therapeutic targets.Although both and secretase activities represent therapeutic targets for the development of novel protease inhibitors for AD, the demonstration that BACE is the principal secretase in cultured neurons and in brain prov ides an excellent rationale for focusing on the design of novel therapeutics to inhibit BACE activity in brain.Importantly, in contrast to PS mice, the BACE mice seem to be normal.Given the role of PS in secretase activity, development of PS inhibitors is an important avenue of investigation for potential therapeutics.Another possibility, not mutually exclusive, is that serum antibodies serve as a sink to draw the amyloid peptide from the brain into the circulation, thus changing the equilibrium of A in different compartments and Diethylstilbestrol promoting removal from the brain.Immunization seems to attenuate learning and behavioral deficits in at least two cohorts of mutant APP mice. It is clear from the studies in mice that achieving adequate levels of antibody titer is critical because these levels predict amyloid clearance in mutant transgenic mice.Amyotrophic lateral sclerosis ALS manifests as muscle weakness and atrophy, along with spastic paralysis, which result from selective degeneration of spinal and corticospinal motor neurons, respectively.The disease affects the size, appearance and metabolism of these cells and evolves in stages.First, neurofilamentous swellings occur in proximal axonal segments accompanied by ubiquitinpositive aggregates.Next, motor axons retract and become disconnected from the denervated muscles.At this stage, trophic support is compromised, and cell bodies shrink and dendrites are attenuated.Neurons die in the final stages and exhibit several characteristics of apoptosis.Ultimately, the numbers of motor neurons in brainstem nuclei and spinal cord are reduced, and large pyramidal neurons in motor cortex are lost.The clinical signs are most closely linked to the disconnection of the synaptic terminals of these neuronal populations from their targets.

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