Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation.

The glycogen synthase kinase-3beta (GSK3beta) pathway plays an important role in mediating neuronal fate and synaptic plasticity. In Alzheimer's disease (AD), abnormal activation of this pathway might play an important role in neurodegeneration, and compounds such as lithium that modulate GSK3beta activity have been shown to reduce amyloid production and tau phosphorylation in amyloid precursor protein (APP) transgenic (tg) mice. However, it is unclear whether regulation of GSK3beta is neuroprotective in APP tg mice. In this context, the main objective of the present study was to determine whether pharmacological or genetic manipulations that block the GSK3beta pathway might ameliorate the neurodegenerative alterations in APP tg mice and to better understand the mechanisms involved. For this purpose, two sets of experiments were performed. First, tg mice expressing mutant human APP under the Thy1 promoter (hAPP tg) were treated with either lithium chloride or saline alone. Second, hAPP tg mice were crossed with GSK3beta tg mice, in which overexpression of this signaling molecule results in a dominant-negative (DN) effect with inhibition of activity. hAPP tg mice that were treated with lithium or that were crossed with DN-GSK3beta tg mice displayed improved performance in the water maze, preservation of the dendritic structure in the frontal cortex and hippocampus, and decreased tau phosphorylation. Moreover, reduced activation of GSK3beta was associated with decreased levels of APP phosphorylation that resulted in decreased amyloid-beta production. In conclusion, the present study showed that modulation of the GSK3beta signaling pathway might also have neuroprotective effects in tg mice by regulating APP maturation and processing and further supports the notion that GSK3beta might be a suitable target for the treatment of AD.

Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease.

Cerebrolysin is a peptide mixture with neurotrophic effects that might reduce the neurodegenerative pathology in Alzheimer's disease (AD). We have previously shown in an amyloid protein precursor (APP) transgenic (tg) mouse model of AD-like neuropathology that Cerebrolysin ameliorates behavioral deficits, is neuroprotective, and decreases amyloid burden; however, the mechanisms involved are not completely clear. Cerebrolysin might reduce amyloid deposition by regulating amyloid-beta (Abeta) degradation or by modulating APP expression, maturation, or processing. To investigate these possibilities, APP tg mice were treated for 6 months with Cerebrolysin and analyzed in the water maze, followed by RNA, immunoblot, and confocal microscopy analysis of full-length (FL) APP and its fragments, beta-secretase (BACE1), and Abeta-degrading enzymes [neprilysin (Nep) and insulin-degrading enzyme (IDE)]. Consistent with previous studies, Cerebrolysin ameliorated the performance deficits in the spatial learning portion of the water maze and reduced the synaptic pathology and amyloid burden in the brains of APP tg mice. These effects were associated with reduced levels of FL APP and APP C-terminal fragments, but levels of BACE1, Notch1, Nep, and IDE were unchanged. In contrast, levels of active cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3beta [GSK-3beta; but not stress-activated protein kinase-1 (SAPK1)], kinases that phosphorylate APP, were reduced. Furthermore, Cerebrolysin reduced the levels of phosphorylated APP and the accumulation of APP in the neuritic processes. Taken together, these results suggest that Cerebrolysin might reduce AD-like pathology in the APP tg mice by regulating APP maturation and transport to sites where Abeta protein is generated. This study clarifies the mechanisms through which Cerebrolysin might reduce Abeta production and deposition in AD and further supports the importance of this compound in the potential treatment of early AD.

Astroglial activation of extracellular-regulated kinase in early stages of Alzheimer disease.

Characterization of the earliest neuropathologic features of Alzheimer disease (AD) indicates that synaptic degeneration accompanied by tau hyperphosphorylation and amyloid deposition might be an important feature. The mechanisms involved are unclear; however, dysregulation of signaling cascades such as the extracellular signal-regulated kinase (ERK) pathway might play a role. In this context, the main objective of this study was to determine whether ERK hyperactivation occurs in early stages of AD. We compared the patterns of total and phosphorylated ERK (pERK) expression in the midfrontal cortex of patients clinically and neuropathologically characterized with early, intermediate, or advanced AD. Immunocytochemical and Western blot analysis showed that in early AD, there was extensive activation of ERK in astroglial cells in the white matter accompanied by intense astrogliosis. In contrast, in patients with more advanced AD, pERK immunoreactivity was associated with neuronal cell bodies and dystrophic neurites around plaques. Levels of astroglial pERK immunoreactivity in the white matter were strongly correlated with scores of cognitive performance (Blessed, Mini-Mental Status Examination, and Clinical Dementia Rating) and with the severity of AD neuropathology (Braak stage). These findings suggest that astroglial ERK activation may be an important early response to the onset of AD pathology. Identification of cell signaling events unique to early AD may provide therapeutic targets for the prevention or delay of dementia.