The mechanisms by which neurons and synapses are lost in Alzheimer's disease (AD) are not completely understood. To characterize potential signaling events linked to AD pathogenesis, activation-specific antibodies were used to examine mitogen-activated protein kinase (MAPK) kinase pathways at various ages in mice transgenic for human amyloid precursor protein-695 with the Swedish familial AD mutations (Tg2576) and homozygous for a P264L familial AD mutation introduced by targeting of the presenilin-1 gene (PS1(P264L)). Although the c-Jun N-terminal kinase (JNK) and p38 pathways were significantly activated in the cortex at both 7 and 12 months of age, there was no significant activation of the extracellular signal-regulated kinase pathway. MAPK kinase-4, an upstream activator of JNK, was also significantly activated at 7 and 12 months, whereas c-Jun, a downstream effector of JNK-associated apoptotic signaling, was not induced. The lack of c-Jun activation is consistent with the absence of neuronal loss in both cortex and hippocampal CA1 at 12 months. The JNK activation was localized to amyloid deposits, within neurites containing phosphorylated tau. Synaptophysin was quantified biochemically as a measure of synaptic integrity and was significantly reduced in an age-dependent manner in the Tg2576/PS1(P264L) cortex but not in either PS1(P264L) or Tg2576 cortex. Stress-responsive MAP kinase pathways were activated in the brain of the Tg2576/PS1(P264L) AD model, and this activation was coincident with the age-dependent increase in amyloid deposition, tau phosphorylation, and loss of synaptophysin.

The pathogenic mechanism linking presenilin-1 (PS-1) gene mutations to familial Alzheimer's disease (FAD) is uncertain, but has been proposed to include increased neuronal sensitivity to degeneration and enhanced amyloidogenic processing of the ␤-amyloid precursor protein (APP). We investigated this issue by using gene targeting with the Cre-lox system to introduce an FAD-linked P264L mutation into the endogenous mouse PS-1 gene, an approach that maintains normal regulatory controls over expression. Primary cortical neurons derived from PS-1 homozygous mutant knock-in mice exhibit basal neurodegeneration similar to their PS-1 wild-type counterparts. Staurosporine and A␤1-42 induce apoptosis, and neither the dose dependence nor maximal extent of cell death is altered by the PS-1 knock-in mutation. Similarly, glutamate-induced neuronal necrosis is unaffected by the PS-1P264L mutation. The lack of effect of the PS-1P264L mutation is confirmed by measures of basal-and toxin-induced caspase and calpain activation, biochemical indices of apoptotic and necrotic signaling, respectively. To analyze the influence of the PS-1P264L knock-in mutation on APP processing and the development of AD-type neuropathology, we created mouse lines carrying mutations in both PS-1 and APP. In contrast to the lack of effect on neuronal vulnerability, cortical neurons cultured from PS-1P264L homozygous mutant mice secrete A␤42 at an increased rate, whereas secretion of A␤40 is reduced. Moreover, the PS-1 knock-in mutation selectively increases A␤42 levels in the mouse brain and accelerates the onset of amyloid deposition and its attendant reactive gliosis, even as a single mutant allele. We conclude that expression of an FAD-linked mutant PS-1 at normal levels does not generally increase cortical neuronal sensitivity to degeneration. Instead, enhanced amyloidogenic processing of APP likely is critical to the pathogenesis of PS-1-linked FAD. Key words: presenilin; amyloid; plaque, neuronal necrosis; neuronal apoptosis; plaque; amyloid precursor protein; A␤; familial Alzheimer's Disease; gene targetingMutations in the ␤-amyloid precursor protein (APP), presenilin-1 (PS-1), and presenilin-2 (PS-2) genes are a leading cause of early onset familial Alzheimer's disease (FAD) and cosegregate with FAD in an autosomal dominant manner (Price et al., 1998;Selkoe, 1998). All forms of AD are characterized by loss of neurons and synapses in specific brain regions, and deposition of protein aggregates as A␤-containing amyloid plaques in the brain parenchyma, leptomeninges, and cerebrovasculature, and as tau-containing intraneuronal neurofibrillary tangles. At least two leading hypotheses have emerged for the pathogenic mechanisms of the mutations. According to the "amyloid cascade" hypothesis, APP and PS mutations promote formation from APP of the highly insoluble A␤42 variant, whose progressive aggregation triggers the amyloid and synaptic abnormalities and neuronal loss. It is supported by findings that all of the FAD-linked mutations examined so far i...

The role of oxidative damage in neurodegenerative disease was investigated in mice lacking cytoplasmic Cu/Zn superoxide dismutase (SOD) , created by deletion of the SOD1 gene (SOD1 ؊/؊ ). SOD1 ؊/؊ mice developed a chronic peripheral hindlimb axonopathy. Mild denervation of muscle was detected at 2 months, and behavioral and physiological motor deficits were present at 5-7 months of age. Ventral root axons were shrunken but were normal in number. The somatosensory system in SOD1 ؊/؊ mice was mildly affected. SOD1؊/؊ mice expressing Cu/Zn SOD only in brain and spinal cord were generated using transgenic mice expressing mouse SOD1 driven by the neuron-specific synapsin promoter. Neuron-specific expression of Cu/Zn SOD in SOD1 ؊/؊ mice rescued motor neurons from the neuropathy. Therefore , Cu/Zn SOD is not required for normal motor neuron survival , but is necessary for the maintenance of normal neuromuscular junctions by hindlimb motor neurons. (Am J Pathol 1999, 155:663-672)

No abstract

All DA releasing agents tested, and some DAT-inhibiting agents, produced RHS at equal wake-promoting doses. Thus amphetamine-like DA release appears sufficient for inducing RHS, but additional properties (pharmacologic and/or pharmacokinetic) evidently underlie RHS of other DAT inhibitors. Enhancing wake while mitigating RHS can be achieved by combining DAT-inhibiting and DA-releasing agents.