Defects in dendritic spines are common to several forms of cognitive deficits, including mental retardation and Alzheimer disease. Because mutation of p21-activated kinase (PAK) can lead to mental retardation and because PAK-cofilin signaling is critical in dendritic spine morphogenesis and actin dynamics, we hypothesized that the PAK pathway is involved in synaptic and cognitive deficits in Alzheimer disease. Here, we show that PAK and its activity are markedly reduced in Alzheimer disease and that this is accompanied by reduced and redistributed phosphoPAK, prominent cofilin pathology and downstream loss of the spine actin-regulatory protein drebrin, which cofilin removes from actin. We found that beta-amyloid (Abeta) was directly involved in PAK signaling deficits and drebrin loss in Abeta oligomer-treated hippocampal neurons and in the Appswe transgenic mouse model bearing a double mutation leading to higher Abeta production. In addition, pharmacological PAK inhibition in adult mice was sufficient to cause similar cofilin pathology, drebrin loss and memory impairment, consistent with a potential causal role of PAK defects in cognitive deficits in Alzheimer disease.

Neutrophil migration inhibition factor from T lymphocytes (NIF-T) is a lymphokine that acts to localize granulocytes. Medium conditioned by the Mo human T-lymphoblast cell line was used to purify NIF-T, a glycoprotein with a molecular weight of 22,000. The NIF-T was found to potently stimulate the growth of granulocyte and macrophage colonies from human bone marrow and colony formation by the KG-1 myeloid leukemia cell line. Thus a human lymphokine (NIF-T) that modulates the activities of mature neutrophilic granulocytes is also a colony-stimulating factor acting on precursors to induce growth and differentiation of new effector cells.

The polymorphonuclear leukocyte (PMN), or neutrophil, is the major host defence cell protecting the body against invasion by bacteria and fungi. Products of oxidative metabolism mediate PMN microbicidal and tumoricidal activity but the mechanisms by which these pathways become activated are not well understood. We have previously described a human granulocyte-macrophage colony-stimulating factor (GM-CSF) of relative molecular mass (Mr) 22,000 that also inhibits neutrophil motility (NIF-T activity). Because of its direct action on granulocytes, this lymphokine is a candidate for a neutrophil-activating factor. We have studied the effect of GM-CSF/NIF-T on superoxide anion generation in response to the bacterial chemo-attractant N-formylmethionyl-leucylphenylalanine (f-MLP), and report here that PMNs preincubated with either purified natural GM-CSF or biosynthetic (recombinant) GM-CSF showed increased (as much as fourfold) superoxide anion production in response to f-MLP. These results indicate that human GM-CSF is a neutrophil-activating factor.

Defects in dendritic spines and synapses contribute to cognitive deficits in mental retardation syndromes and, potentially, Alzheimer disease. p21-activated kinases (PAKs) regulate actin filaments and morphogenesis of dendritic spines regulated by the Rho family GTPases Rac and Cdc42. We previously reported that active PAK was markedly reduced in Alzheimer disease cytosol, accompanied by downstream loss of the spine actinregulatory protein Drebrin. ␤-Amyloid (A␤) oligomer was implicated in PAK defects. Here we demonstrate that PAK is aberrantly activated and translocated from cytosol to membrane in Alzheimer disease brain and in 22-month-old Tg2576 transgenic mice with Alzheimer disease. This active PAK coimmunoprecipitated with the small GTPase Rac and both translocated to granules. A␤ 42 oligomer treatment of cultured hippocampal neurons induced similar effects, accompanied by reduction of dendrites that were protected by kinase-active but not kinase-dead PAK. A␤ 42 oligomer treatment also significantly reduced N-methyl-D-aspartic acid receptor subunit NR2B phosphotyrosine labeling. The Src family tyrosine kinase inhibitor PP2 significantly blocked the PAK/Rac translocation but not the loss of p-NR2B in A␤ 42 oligomer-treated neurons. Src family kinases are known to phosphorylate the Rac activator Tiam1, which has recently been shown to be A␤-responsive. In addition, anti-oligomer curcumin comparatively suppressed PAK translocation in aged Tg2576 transgenic mice with Alzheimer amyloid pathology and in A␤ 42 oligomer-treated cultured hippocampal neurons. Our results implicate aberrant PAK in A␤ oligomer-induced signaling and synaptic deficits in Alzheimer disease. Cognitive deficits in Alzheimer disease (AD)2 correlate with progressive synaptic dysfunction and loss that may be initiated by soluble ␤-amyloid peptide 1-42 (A␤ 42 ) and driven further by the accumulating neuropathological hallmarks, including intraneuronal neurofibrillary tangles, extracellular amyloid plaques, and neuron loss. Soluble A␤ or A␤ oligomers correlate highly with synapse loss (1, 2) and the degree of dementia (3). They also potently inhibit long term potentiation (LTP) in vivo (4). A␤-induced synaptic dysfunction likely contributes to cognitive deficits in several different AD transgenic mouse models (5-7).Both dystrophic neurites and dendritic spine loss are observed in AD and many mental retardation syndromes (8 -10). Dendritic spines, major sites of synaptic contacts, are structurally reliant on the actin cytoskeleton. p21-activated kinases (PAK) (11) are a family of serine/threonine protein kinases involved in regulating the actin-severing protein cofilin, the actin cytoskeleton, and dendritic function as downstream effectors of Rac1/Cdc42 (12). Thus, the small GTPases (Rho, Rac, and Cdc42) play critical roles in regulating dendrite initiation, growth, branching, spinogenesis, and spine maintenance (13-15). Mutations in PAK3 are associated with X-linked nonsyndromic forms of mental retardation, in which the only distinctive clinica...