A subset of B lymphocytes present primarily in the peritoneal and pleural cavities is defined by the expression of CD5 and is elevated in autoimmune diseases. Upon signaling through membrane immunoglobulin M (mIgM), splenic B lymphocytes (B-2) proliferate, whereas peritoneal B cells (B-1) undergo apoptosis. However, in CD5-deficient mice, B-1 cells responded to mIgM crosslinking by developing a resistance to apoptosis and entering the cell cycle. In wild-type B-1 cells, prevention of association between CD5 and mIgM rescued their growth response to mIgM crosslinking. Thus the B cell receptor-mediated signaling is negatively regulated by CD5 in normal B-1 cells.
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.
Background: Traumatic brain injury (TBI) is an environmental risk factor for developing Alzheimer disease. This may be due, in part, to changes associated with -amyloid (A) plaque formation, which can occur within hours after injury, regardless of the patient's age. In addition to being precursors of toxic fibrils that deposit into plaques, soluble (nonfibrillar) A peptides are posited to disrupt synaptic function and are associated with cognitive decline in Alzheimer disease. Changes in soluble A levels and their relationship to A plaque formation following TBI are unknown.Objective: To quantify brain tissue levels of soluble A peptides and their precursor protein in relation to A plaque formation after TBI in humans.Design: Surgically resected temporal cortex tissue from patients with severe TBI was processed for biochemical assays of soluble A peptides with COOH-termini ending in amino acid 40 (A 40 ) or 42 (A 42 ) and A precur-sor protein to compare patients with cortical A plaques and those without.Patients: Nineteen subjects admitted to the University of Pittsburgh Medical Center for treatment of severe closed head injury.Results: Patients with severe TBI and cortical plaques had higher levels of soluble A 1-42 but not A 1-40 ; half of them were apolipoprotein E (APOE) ε4 allele carriers. The lowest A levels were in 1 patient without plaques who was the only subject with an APOE ε2 allele. -Amyloid precursor protein levels were comparable in the 2 TBI groups.Conclusions: Selective increases in soluble A 1-42 after TBI may predispose individuals with a brain injury to Alzheimer disease pathology. This may be influenced by the APOE genotype, and it may confer increased risk for developing Alzheimer disease later in life.
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