Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling.

The role of presenilin-1 (PS1) in neuronal phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in primary neuronal cultures from wild-type (WT) and PS1 null (PS1-/-) embryonic mouse brains. Here we show that in PS1-/- cultures, the onset of neuronal maturation coincides with a decrease in the PI3K-dependent phosphorylation-activation of Akt and phosphorylation-inactivation of glycogen synthase kinase-3 (GSK-3). Mature PS1-/- neurons show increased activation of apoptotic caspase-3 and progressive degeneration preceded by dendritic retraction.

Genetic and molecular aspects of Alzheimer's disease shed light on new mechanisms of transcriptional regulation.

Rapid advances made in biological research aimed at understanding the molecular basis of the pathogenesis of Alzheimer's disease have led to the characterization of a novel catalytic activity termed gamma-secretase. First described for its beta-amyloid-producing function, gamma-secretase is now actively studied for its role in a novel signal transduction paradigm, which implicates cell-surface receptor proteolysis and direct surface-to-nucleus signal transduction. gamma-Secretase targets numerous type I protein receptors involved in diverse functions ranging from normal development to neurodegeneration.

Changes of internal state are expressed in coherent shifts of neuromuscular activity in Aplysia feeding behavior.

The multitasking central pattern generator (CPG) that drives consummatory feeding behaviors of Aplysia can produce ingestive, egestive, and intermediate motor programs. External stimuli trigger the programs but, remarkably, do not directly specify which type of program is produced. Rather, recent work has proposed, the type of program is determined by the internal network state of the CPG that has developed in response to the previous history of the stimulation.

Aging-related changes in ovarian hormones, their receptors, and neuroendocrine function.

Ovarian steroid hormones exert a broad range of effects on the body and brain. In the nervous system, estrogen and progesterone have crucial feedback actions on the hypothalamic neurons that drive the reproductive axis. In addition, hormones exert a variety of actions on other traditionally nonreproductive functions such as cognition, learning and memory, neuroprotection, mood and affective behavior, and locomotor activity.

Modeling neuromuscular modulation in Aplysia. III. Interaction of central motor commands and peripheral modulatory state for optimal behavior.

Recent work in computational neuroethology has emphasized that "the brain has a body": successful adaptive behavior is not simply commanded by the nervous system, but emerges from interactions of nervous system, body, and environment. Here we continue our study of these issues in the accessory radula closer (ARC) neuromuscular system of Aplysia. The ARC muscle participates in the animal's feeding behaviors, a set of cyclical, rhythmic behaviors driven by a central pattern generator (CPG).

Retrieving memories via internal context requires the hippocampus.

Episodic memory encodes the unique contexts of events so that people can remember the details of an experience when cued by only a subset of event features (Tulving, 1972). In humans, the hippocampus is crucial for this kind of memory (Scoville and Milner, 1957; Vargha-Khadem et al., 1997).

The nature and effects of cortical microvascular pathology in aging and Alzheimer's disease.

Age-related and amyloid-induced pathology of the cerebral microvasculature have been implicated as potential contributing factors to the pathogenesis of Alzheimer's disease (AD). The microvasculature plays a crucial role in maintaining brain homeostasis and deterioration of its integrity may have deleterious effects on brain function in AD, possibly leading to neurofibrillary degeneration, plaque formation, and cell loss. Brain vessels possess peculiar anatomical and physiological properties owing to their role in the exchange processes of various substances between blood and brain, which are highly regulated for the maintenance of ionic homeostasis of the neuronal environment.

Reduction in hippocampal cholinergic innervation is unrelated to recognition memory impairment in aged rhesus monkeys.

Alterations in the basal forebrain cholinergic system have been widely studied in brain aging and Alzheimer's disease, but the magnitude of decline and relationship to cognitive impairment are still a matter of debate. The rhesus monkey (Macaca mulatta) provides a compelling model to study age-related memory decline, as the pattern of impairment closely parallels that observed in humans. Here, we used antibodies against the vesicular acetylcholine transporter and a new stereological technique to estimate total cholinergic fiber length in hippocampal subregions of behaviorally characterized young and aged rhesus monkeys.

PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations.

Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by activating its downstream effector Akt kinase. Here we show that PS1, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling. This function of PS1 is unaffected by gamma-secretase inhibitors.

Mining microarrays for metabolic meaning: nutritional regulation of hypothalamic gene expression.

DNA microarray analysis has been used to investigate relative changes in the level of gene expression in the CNS, including changes that are associated with disease, injury, psychiatric disorders, drug exposure or withdrawal, and memory formation. We have used oligonucleotide microarrays to identify hypothalamic genes that respond to nutritional manipulation. In addition to commonly used microarray analysis based on criteria such as fold-regulation, we have also found that simply carrying out multiple t tests then sorting by P value constitutes a highly reliable method to detect true regulation, as assessed by real-time polymerase chain reaction (PCR), even for relatively low abundance genes or relatively low magnitude of regulation.

Structure of the neural (N-) cadherin prodomain reveals a cadherin extracellular domain-like fold without adhesive characteristics.

Classical cadherins mediate cell-cell adhesion through calcium-dependent homophilic interactions and are activated through cleavage of a prosequence in the late Golgi. We present here the first three-dimensional structure of a classical cadherin prosequence, solved by NMR. The prototypic prosequence of N-cadherin consists of an Ig-like domain and an unstructured C-terminal region.

Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex.

Both the hippocampus and the medial prefrontal cortex (mPFC) play an important role in the negative feedback regulation of hypothalamic-pituitary-adrenal (HPA) activity during physiologic and behavioral stress. Moreover, chronic behavioral stress is known to affect the morphology of CA3c pyramidal neurons in the rat, by reducing total branch number and length of apical dendrites. In the present study, we investigated the effects of behavioral stress on the mPFC, using the repeated restraint stress paradigm.

The hypothalamic insulin-like growth factor-1 receptor and its relationship to gonadotropin-releasing hormones neurones during postnatal development.

Reproduction in vertebrates is controlled by hypophysiotropic gonadotropin-releasing hormone (GnRH) neurones. Pulsatile GnRH release increases during reproductive development, resulting in the onset and progression of puberty and, ultimately, the acquisition and maintenance of adult reproductive function. These changes in GnRH release are largely due to inputs to GnRH cells from other factors, including the neurotrophic factor, insulin-like growth factor-1 (IGF-1).

Estrogen replacement increases spinophilin-immunoreactive spine number in the prefrontal cortex of female rhesus monkeys.

While studies have shown that estrogen affects hippocampal spine density and function, behavioral studies in humans and nonhuman primates have also implicated the prefrontal cortex in the effects of estrogen on cognition. However, the potential for similar estrogen-induced increases in spines and synapses in the prefrontal cortex has not been investigated in primates. Moreover, it is not known if such an estrogen effect would be manifested throughout the neocortex or primarily in the regions involved in cognition.

Prospective and retrospective memory coding in the hippocampus.

The effect of memory on hippocampal neuronal activity was assessed as rats performed a spatial task that was impaired by fornix lesions. The influences of current location, recently entered places, and places about to be entered were compared. Three new findings emerged.

Estrogen and the aging hippocampal synapse.

The ramifications of endocrine and neural senescence converge in the hippocampus, particularly with respect to glutamatergic synapses. In this review, we will focus on current literature suggesting that potential synaptic alterations induced by estrogen in the hippocampus are mediated through interactions between ER-alpha and NMDA receptors. In addition, we will examine the data suggesting that these interactions may be uncoupled with aging.

Expression of VGF mRNA in developing neuroendocrine and endocrine tissues.

Analysis of knockout mice suggests that the neurotropin-inducible secreted polypeptide VGF (non-acronymic) plays an important role in the regulation of energy balance. VGF is synthesized by neurons in the central and peripheral nervous systems (CNS, PNS), as well as in the adult pituitary, adrenal medulla, endocrine cells of the stomach and pancreatic beta cells. Thus VGF, like cholecystokinin, leptin, ghrelin and other peptide hormones that have been shown to regulate feeding and energy expenditure, is synthesized in both the gut and the brain.

Stereologic analysis of estrogen receptor alpha (ER alpha) expression in rat hypothalamus and its regulation by aging and estrogen.

The estrogen receptor alpha (ERalpha) in the hypothalamus plays important roles in the regulation of reproductive development, physiology, and behavior. However, the expression of the ERalpha may change during aging or in response to varying estrogen levels. The present study measured changes in the numbers of ERalpha-expressing cells in specific hypothalamic and preoptic nuclei of ovariectomized female Sprague-Dawley rats at three ages (young [3-4 months], middle-aged [10-12 months], or old [24-26 months]) and with or without estrogen replacement.

A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations.

Presenilin1 (PS1), a protein implicated in Alzheimer's disease (AD), forms complexes with N-cadherin, a transmembrane protein with important neuronal and synaptic functions. Here, we show that a PS1-dependent gamma-secretase protease activity promotes an epsilon-like cleavage of N-cadherin to produce its intracellular domain peptide, N-Cad/CTF2. NMDA receptor agonists stimulate N-Cad/CTF2 production suggesting that this receptor regulates the epsilon-cleavage of N-cadherin.

Estrogen increases the number of spinophilin-immunoreactive spines in the hippocampus of young and aged female rhesus monkeys.

It is well documented that estrogen increases dendritic spine density in CA1 pyramidal cells of young female rats. However, this effect is attenuated in aged rats. We report here a quantitative analysis of estrogen effects on hippocampal spine number as visualized with antispinophilin in young (6-8 years old) and aged (19-23 years old) female rhesus monkeys, a species with a pattern of female endocrine senescence comparable to that of humans.

The fatty acid synthase inhibitor cerulenin and feeding, like leptin, activate hypothalamic pro-opiomelanocortin (POMC) neurons.

Hypothalamic POMC neurons mediate catabolic responses such as decreased food intake and increased energy expenditure by, in part, monitoring levels of metabolic factors such as glucose, insulin and leptin. Recently, fatty acid synthase inhibitors were reported to reduce body weight, inhibit food intake, and increase metabolic rate, possibly by acting on hypothalamic neurons through a mechanism involving malonyl-CoA accumulation. Given the observation that leptin mediates similar catabolic effects by, in part, activating hypothalamic POMC neurons, it is possible that other catabolic signals such as feeding and fatty acid synthase inhibition may also activate POMC neurons.

Age-related changes in estrogen receptor beta in rat hypothalamus: a quantitative analysis.

Although the estrogen receptor beta (ER beta) is a major target for actions of estrogen on the brain, little is known about its neural expression during aging, when levels and the mode of estrogen release undergo substantial changes. Therefore, in the present study we examined effects of aging and estrogen treatment on the number of cells expressing the ER beta in female rats. Two regions relevant to reproductive function were analyzed: the anteroventral periventricular nucleus (AVPV) and the principal nucleus of the bed nucleus of the stria terminalis (pBST).

Age-related dendritic and spine changes in corticocortically projecting neurons in macaque monkeys.

Alterations in neuronal morphology occur in primate cerebral cortex during normal aging, vary depending on the neuronal type, region and cortical layer, and have been related to memory and cognitive impairment. We analyzed how such changes affect a specific subpopulation of cortical neurons forming long corticocortical projections from the superior temporal cortex to prefrontal area 46. These neurons were identified by retrograde transport in young and old macaque monkeys.

ERMs colocalize transiently with L1 during neocortical axon outgrowth.

L1 is a member of the Ig superfamily of cell adhesion molecules (CAMs) that functions in many aspects of neuronal development including axonal outgrowth and neuronal migration. These functions require coordination between L1 and the actin cytoskeleton. Because CAMs and the cytoskeleton do not bind directly, membrane-cytoskeletal linkers (MCLs) such as ankyrin are thought to be crucial to their interactions, but data from a knockout mouse suggest that ankyrin is not necessary for the earliest events attributed to L1 function.