Interaction of ASK1 and the beta-amyloid precursor protein in a stress-signaling complex.

The amyloid precursor protein (APP) is a type I transmembrane protein translocated to neuronal terminals, whose function is still unknown. The C-terminus of APP mediates its interaction with cellular adaptor and signaling proteins, some of which signal to the stress-activated protein kinase (SAPK) pathway. Here we show that ASK1, a MAPKKK that activates two SAPKs, c-Jun N-terminal-kinase (JNK) and p38, is present in a complex containing APP, phospho-MKK6, JIP1 and JNK1.

A pilot proteomic study of amyloid precursor interactors in Alzheimer's disease.

Several approaches have been used in an effort to identify proteins that interact with beta-amyloid precursor protein (APP). However, few studies have addressed the identification of proteins associated with APP in brain tissue from patients with Alzheimer's disease. We report the results of a pilot proteomic study performed on complexes immunoprecipitated with APP in brain samples of patients with Alzheimer's disease and normal control subjects.

Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat.

Cell replacement therapy may have the potential to promote brain repair and recovery after stroke. To compare how focal cerebral ischemia affects the entry, migration, and phenotypic features of neural precursor cells transplanted by different routes, we administered neuronal precursors from embryonic cerebral cortex of green fluorescent protein (GFP)-expressing transgenic mice to rats that had undergone middle cerebral artery occlusion (MCAO) by the intrastriatal, intraventricular, and intravenous routes. MCAO increased the entry of GFP-immunoreactive cells, most of which expressed neuroepithelial (nestin) or neuronal (doublecortin) markers, from the ventricles and bloodstream into the brain, and enhanced their migration when delivered by any of these routes.

Tau phosphorylation in Alzheimer's disease: potential involvement of an APP-MAP kinase complex.

The two predominant pathological concomitants of Alzheimer's disease (AD) are senile plaques and neurofibrillary tangles. Although many biochemical studies have addressed the composition and formation of these AD hallmarks, very little is known about the interrelationship between the two. Here we present evidence that the tau phosphorylation characteristic of neurofibrillary tangles may be mediated by a physical association of MKK6 (mitogen-associated protein kinase kinase 6) with tau and subsequent phosphorylation of tau by the MKK6 substrate, p38 MAPK; and that APP (beta-amyloid precursor protein) may be co-immunoprecipitated both with MKK6 and its upstream MAPKKK, ASK1.

Effect of aging on neuroglobin expression in rodent brain.

Neuroglobin (Ngb), a recently discovered O2-binding heme protein related to hemoglobin and myoglobin, protects neurons from hypoxic-ischemic injury in vitro and in vivo. In immunostained mouse brain sections, we found widespread expression of Ngb protein in neurons, but not astrocytes, of several brain regions that are prominently involved in age-related neurodegenerative disorders. Western blots from young adult (3 month), middle-aged (12 month), and aged (24 month) rats showed an age-related decline in Ngb expression in cerebral neocortex, hippocampus, caudate-putamen, and cerebellum.

PKR activation in neurodegenerative disease.

Interferon-inducible, double-stranded RNA-dependent protein kinase PKR is well known as an early cellular responder to viral infection. Activation of PKR has been associated with a number of downstream cell stress and cell death events, including a generalized shutdown of protein translation, activation of caspase-8, participation in JNK and p38 MAPK pathways, activation of NF-kappaB, etc. Recently, the activation of PKR has also been described in several neurodegenerative diseases, including Huntington disease, Alzheimer disease, and amyotrophic lateral sclerosis.

Proteomic and immunochemical characterization of a role for stathmin in adult neurogenesis.

Stathmin is a developmentally regulated cytosolic protein expressed at high levels in the brain. Two-dimensional differential in-gel electrophoresis and mass spectroscopy of proteins expressed in immature and mature cultures from embryonic rat cerebral cortex identified stathmin among several differentially expressed proteins, consistent with a possible role in neurogenesis. Stathmin immunohistochemistry in adult rodent brain revealed prominent expression in neuroproliferative zones and neuronal migration pathways, a pattern that resembles the expression of doublecortin, which is implicated in neuronal migration.

Increased hippocampal neurogenesis in Alzheimer's disease.

Neurogenesis, which persists in the adult mammalian brain, may provide a basis for neuronal replacement therapy in neurodegenerative diseases like Alzheimer's disease (AD). Neurogenesis is increased in certain acute neurological disorders, such as ischemia and epilepsy, but the effect of more chronic neurodegenerations is uncertain, and some animal models of AD show impaired neurogenesis. To determine how neurogenesis is affected in the brains of patients with AD, we investigated the expression of immature neuronal marker proteins that signal the birth of new neurons in the hippocampus of AD patients.

Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum.

Pathological processes, including cerebral ischemia, can enhance neurogenesis in the adult brain, but the fate of the newborn neurons that are produced and their role in brain repair are obscure. To determine if ischemia-induced neuronal proliferation is associated with migration of nascent neurons toward ischemic lesions, we mapped the migration of cells labeled by cell proliferation markers and antibodies against neuronal marker proteins, for up to 2 weeks after a 90-min episode of focal cerebral ischemia caused by occlusion of the middle cerebral artery. Doublecortin-immunoreactive cells in the rostral subventricular zone, but not the dentate gyrus, migrated into the ischemic penumbra of the adjacent striatum and, via the rostral migratory stream and lateral cortical stream, into the penumbra of ischemic cortex.

Activation of the cell stress kinase PKR in Alzheimer's disease and human amyloid precursor protein transgenic mice.

Accumulation of amyloid beta peptides (Abeta) in the brain, which is a hallmark of Alzheimer's disease (AD), is associated with progressive damage to neuronal processes resulting in extensive neuritic dystrophy. This process may contribute to cognitive decline, but it is not known how Abeta elicits neuritic injury. Our analysis of AD brains and related transgenic mouse models suggests an involvement of the interferon-induced serine-threonine protein kinase, PKR, which is best known for its activation upon binding to double-stranded RNA.

Neuroglobin protects the brain from experimental stroke in vivo.

Neuroglobin (Ngb) is an O(2)-binding protein localized to cerebral neurons of vertebrates, including humans. Its physiological role is unknown but, like hemoglobin, myoglobin, and cytoglobin/histoglobin, it may transport O(2), detoxify reactive oxygen species, or serve as a hypoxia sensor. We reported recently that hypoxia stimulates transcriptional activation of Ngb in cultured cortical neurons and that antisense inhibition of Ngb expression increases hypoxic neuronal injury, whereas overexpression of Ngb confers resistance to hypoxia.

Neonatal porcine pancreatic cell clusters as a potential source for transplantation in humans: characterization of proliferation, apoptosis, xenoantigen expression and gene delivery with recombinant AAV.

Neonatal porcine islets are characterized by reproducible isolation success and high yields, sizable advantages over adult islets. In this work we have analyzed selected phenotypic and functional characteristics of porcine neonatal islets relevant to their possible use for transplant in humans. We show that porcine islet cells proliferate in culture, and synthesize and store islet-specific hormones.

Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78.

Alterations in Ca(2+) homeostasis and accumulation of unfolded proteins in the endoplasmic reticulum (ER) lead to an ER stress response. Prolonged ER stress may lead to cell death. Glucose-regulated protein (GRP) 78 (Bip) is an ER lumen protein whose expression is induced during ER stress.