No abstract

The discovery that some cases of familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) has focused much attention on the function of SOD1 as related to motor neuron survival. Here we describe the creation and characterization of mice completely deficient for this enzyme. These animals develop normally and show no overt motor deficits by 6 months in age. Histological examination of the spinal cord reveals no signs of pathology in animals 4 months in age. However Cu/Zn SOD-deficient mice exhibit marked vulnerability to motor neuron loss after axonal injury. These results indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury.

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The CBA mouse shows little evidence of hearing loss until late in life, whereas the C57BL/6 strain develops a severe and progressive, high-frequency sensorineural hearing loss beginning around 3-6 months of age. These functional differences have been linked to genetic differences in the amount of hair cell loss as a function of age; however, a precise quantitative description of the sensory cell loss is unavailable. The present study provides mean values of inner hair cell (IHC) and outer hair cell (OHC) loss for CBA and C57BL/6 mice at 1, 3, 8, 18, and 26 months of age. CBA mice showed little evidence of hair cell loss until 18 months of age. At 26 months of age, OHC losses in the apex and base of the cochlea were approximately 65% and 50%, respectively, and IHC losses were approximately 25% and 35%. By contrast, C57BL/6 mice showed approximately a 75% OHC and a 55% IHC loss in the base of the cochlea at 3 months of age. OHC and IHC losses increased rapidly with age along a base-to-apex gradient. By 26 months of age, more than 80% of the OHCs were missing throughout the entire cochlea; however, IHC losses ranged from 100% near the base of the cochlea to approximately 20% in the apex.

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.