Nicastrain, a type I transmembrane glycoprotein, is another important component of this complex.Some of the mutant APP mice, although they do not reproduce the full phenotype of AD, represent excellent models of A amyloidosis.The severity is influenced by the level of transgene expression and the specific mutation.In addition to A deposits, these Mofezolac plaques contain neurites, astrocytes and microglia; however, neurofibrillary tangles are not present.A variety of defects are found in different mutant lines, including mild loss of neurons, learning deficits, problems in object recognition memory, and problems with alternationspatial reference and working memory.Interestingly, synaptic abnormalities in hippocampal circuits seem to precede the deposition of A into plaques. Appropriate mouse models that display both amyloid plaques and neurofibrillary tangles have not been entirely successful.In an attempt to obtain mice with both plaques and tangles, mutant APP transgenic mice were mated to mice expressing the PL tau mutant, a mutation Mofezolac linked to familial frontotemporal dementia with parkinsonism. Although these lines do have more tangles, mice bearing both mutant tau and APP are problematic as a faithful model of FAD because the FTDP mutation alone is associated with increased tangles.Similarly, tau pathology can be induced by introducing A fibril into PL tau mutant mice.More appropriate models of AD might require coexpression of mutant APP and all six isoforms of wild type human tau.Mice expressing both mutant PS and mutant APP develop accelerated A amyloidosis in the central nervous system.Mutations known to be more malignant in the human disorder also produce accelerated A deposition in mouse models.These mice also demonstrate that the key participants in A amyloidosis are colocalized in neur ites immediately proximal to sites of A formation in brain, supporting the concept of a neuronal origin for A. This approach is somewhat problematic with regard to APP because of the homologous amyloid precursorlike proteins, APLP and APLP.Homozygous APP mice are viable and fertile, but seem to have subtle decreases in locomotor activity and forelimb grip strength.The absence of substantial phenotypes in APP mice may be related to functional redundancy of APLP and APLP.Consistent with this idea, APLP mice appear normal, but mice with either both APP and APLP targeted alleles or both APLP and APLP null alleles show significant postnatal lethality.Similar approaches have focused on the proteins implicated in and secretase activities.Arrows indicate secretase, BACE, and secretase cleavage sites.Note that secretase or BACE cleaves APP within the A domain, precluding the formation of amyloidogenic A peptides.Mutations within the A domain seemed to enhance A oligomer or protofibril formation.However, it is clear that PS is involved in secretase activity; in cell culture, deletion of PS, or substitution of par ticular aspar tate residues, leads to reduced levels of secretase cleavage products and levels of A. PS null mice areviable and fertile, though they develop ageassociated mild pulmonary fibrosis and hemorrhage.As expected, the absence of PS resulted in decreased A generation, further establishing that PS is critical for secretase activity in the brain.The finding that these forebrainspecific PS knockout mice do not have significant morphological, physiological or overt behavioral abnormalities suggest that secretase inhibitors may be useful as therapeutic agents for A amyloidosis.

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