17Beta-estradiol protects depletion of rat temporal cortex somatostatinergic system by beta-amyloid

Estradiol prevents amyloid-beta peptide (Abeta)-induced cell death through estrogen receptors (ERs) and modulates somatostatin (SRIF) responsiveness in the rat brain. As intracerebroventricular (ICV) Abeta25-35 administration reduces SRIFergic tone in the temporal cortex of ovariectomized (Ovx) rats, we asked whether 17beta-estradiol (E2) treatment can restore the Abeta25-35 induced changes in SRIF content, SRIF receptor density and adenylyl cyclase (AC) activity, as well as if these effects are mediated by ERs. E2 treatment did not change Abeta25-35 levels in the temporal cortex, but partially restored the SRIFergic parameters affected by Abeta insult and decreased cell death, which was correlated with Akt activation. The ER antagonist ICI 182,780 prevented the protective effect of E2 on sst2 levels, but did not modify SRIF levels. Furthermore, ICI 182,780 treatment further decreased sst2 protein and mRNA levels when administered alone to Abeta25-35-treated rats, suggesting that it may block the effects of endogenous estrogens. These findings indicate that E2 protects the temporal cortical SRIFergic system from Abeta-induced depletion independently of Abeta accumulation.     

Minocycline provides protection against beta-amyloid(25-35)-induced alterations of the somatostatin signaling pathway in the rat temporal cortex

Minocycline is a semi-synthetic second-generation tetracycline known to improve cognition in amyloid precursor protein transgenic mice. Whether it can protect the somatostatin (SRIF) receptor-effector system, also involved in learning and memory, from alterations induced by chronic i.c.v. infusion of beta-amyloid peptide (Abeta)(25-35) is presently unknown. Hence, in the present study, we tested the effects of minocycline on the SRIF signaling pathway in the rat temporal cortex. To this end, male Wistar rats were injected with minocycline (45 mg/kg body weight) i.p. twice on the first day of treatment. On the following day and during 14 days, Abeta(25-35) was administered i.c.v. via an osmotic minipump connected to a cannula implanted in the left lateral ventricle (300 pmol/day). Minocycline (22.5 mg/kg, i.p.) was injected once again the last 2 days of the Abeta(25-35) infusion. The animals were killed by decapitation 24 h after the last drug injection. Our results show that minocycline prevents the decrease in SRIF receptor density and somatostatin receptor (sst) 2 expression and the attenuated capacity of SRIF to inhibit adenylyl cyclase (AC) activity, alterations present in the temporal cortex of Abeta(25-35)-treated rats. Furthermore, minocycline blocks the Abeta(25-35)-induced decrease in phosphorylated cyclic AMP (cAMP) response element binding protein (p-CREB) content and G-protein-coupled receptor kinase 2 (GRK) protein expression in this brain area. Altogether, the present data demonstrate that minocycline in vivo provides protection against Abeta-induced impairment of the SRIF signal transduction pathway in the rat temporal cortex and suggest that it may have a potential as a therapeutic agent in human Alzheimer's disease, although further studies are warranted.     

The women's health initiative estrogen replacement therapy is neurotrophic and neuroprotective

The current study investigated the neurotrophic and neuroprotective action of the complex formulation of conjugated equine estrogens (CEEs), the most frequently prescribed estrogen replacement therapy in the United States and the estrogen replacement therapy of the Women's Health Initiative. Morphologic analyses demonstrated that CEEs significantly increased neuronal outgrowth in hippocampal, basal forebrain, occipital, parietal and frontal cortex neurons. Dose-response analyses indicated that the lowest effective concentration of CEEs exerted the maximal neurotrophic effect with greatest potency occurring in hippocampal and occipital cortex neurons. CEES induced highly significant neuroprotection against beta amyloid(25-35), hydrogen peroxide and glutamate-induced toxicity. Rank order of potency and magnitude of CEE-induced neuroprotection in the brain regions investigated was hippocampal neurons > basal forebrain neurons > cortical neurons. In hippocampal neurons pre-exposed to beta amyloid(25-35), CEEs halted Abeta(25-35)-induced cell death and protected surviving neurons from further cell death induced by Abeta(25-35). Because CEEs are the estrogen replacement therapy of the Women's Health Initiative, results of the current study could provide cellular mechanisms for understanding effects of CEEs on cognitive function and risk of Alzheimer's disease derived from this prospective clinical trial.     

Attenuation of amyloid beta (Abeta)-induced inhibition of phosphatidylinositol 4-kinase activity by Abeta fragments, Abeta20-29 and Abeta31-35

We previously reported that pathophysiological concentrations of amyloid beta protein (Abeta25-35, 0.1-10 nM) directly inhibited type II phosphatidylinositol 4-kinase (PI4KII) activity in neuronal plasma membranes, which resulted in the enhanced glutamate neurotoxicity. In the present study, we examined the effects of Abeta fragments, Abeta20-29 and Abeta31-35, on the 10 nM Abeta25-35- or Abeta1-42-induced inhibition of PI4KII activity. Both of the peptide fragments recovered the inhibition of rat brain plasma membrane PI4KII activity over the concentration range of 0.1-5 nM. Such protection by the Abeta fragments was observed in the 10 nM Abeta25-35-induced inhibition of recombinant human PI4KII, suggesting that these Abeta fragments blocked the inhibition on PI4KII molecule. The Abeta25-35-induced enhancement of glutamate neurotoxicity was also completely inhibited in the presence of these fragments. Thus, Abeta20-29 and Abeta31-35 ameliorated the Abeta-enhanced glutamate neurotoxicity probably through attenuation of Abeta-induced inhibition of PI4KII activity.     

Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults

Air pollution is a serious environmental problem. We investigated whether residency in cities with high air pollution is associated with neuroinflammation/neurodegeneration in healthy children and young adults who died suddenly. We measured mRNA cyclooxygenase-2, interleukin-1beta, and CD14 in target brain regions from low (n = 12) or highly exposed residents (n = 35) aged 25.1 +/- 1.5 years. Upregulation of cyclooxygenase-2, interleukin-1beta, and CD14 in olfactory bulb, frontal cortex, substantia nigrae and vagus nerves; disruption of the blood-brain barrier; endothelial activation, oxidative stress, and inflammatory cell trafficking were seen in highly exposed subjects. Amyloid beta42 (Abeta42) immunoreactivity was observed in 58.8% of apolipoprotein E (APOE) 3/3 < 25 y, and 100% of the APOE 4 subjects, whereas alpha-synuclein was seen in 23.5% of < 25 y subjects. Particulate material (PM) was seen in olfactory bulb neurons, and PM < 100 nm were observed in intraluminal erythrocytes from lung, frontal, and trigeminal ganglia capillaries. Exposure to air pollution causes neuroinflammation, an altered brain innate immune response, and accumulation of Abeta42 and alpha-synuclein starting in childhood. Exposure to air pollution should be considered a risk factor for Alzheimer's and Parkinson's diseases, and carriers of the APOE 4 allele could have a higher risk of developing Alzheimer's disease if they reside in a polluted environment.     

A vitamin A-free diet results in impairment of the rat hippocampal somatostatinergic system

Previous studies have revealed the presence of retinoid specific receptors in the hippocampus and have demonstrated that vitamin A deficiency produces a severe deficit in spatial learning and memory which are linked to a proper hippocampal functioning. It is also well known that the tetradecapeptide somatostatin binds to specific receptors in the hippocampus and, when injected into this brain area, facilitates the acquisition of spatial tasks. In addition, depletion of somatostatin by cysteamine impairs acquisition of these tasks. Taken together, these studies support the idea that the hippocampal somatostatinergic system might be regulated by vitamin A. Hence, we evaluated the effects of vitamin A deprivation and subsequent administration of vitamin A on the rat hippocampal somatostatinergic system. Rats fed a vitamin A-free diet exhibited a significant reduction of somatostatin-like immunoreactivity content in the hippocampus whereas the somatostatin mRNA levels were unaltered. Vitamin A deficiency increased the somatostatin receptor density and its dissociation constant. Functional Gi activity as well as the capacity of somatostatin to inhibit basal and forskolin-stimulated adenylyl cyclase activity was decreased in vitamin A deficiency rats as compared with the control animals. All these parameters were fully restored when vitamin A was replaced in the diet. Furthermore, we found that the Gialpha1, Gialpha2 and Gialpha3 protein levels were unaltered in hippocampal membranes from rats fed a vitamin A-free diet whereas subsequent vitamin A administration to these rats caused a significant increase in the levels of Gialpha1 and Gialpha2. Altogether, the present findings suggest that dietary vitamin A levels modulate the somatostatinergic system in the rat hippocampus.     

Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss

To analyze the relationship between the deposition of amyloid beta peptides (Abeta) and neuronal loss in transgenic models of Alzheimer's disease (AD), we examined the frontal neocortex (Fc) and CA1 portion of hippocampus (CA1) in PSAPP mice doubly expressing AD-associated mutant presenilin 1 (PS1) and Swedish-type mutant beta amyloid precursor protein (APPsw) by morphometry of Abeta burden and neuronal counts. Deposition of Abeta was detected as early as 3 months of age in the Fc and CA1 of PSAPP mice and progressed to cover 28.3% of the superior frontal cortex and 18.4% of CA1 at 12 months: approximately 20- (Fc) and approximately 40- (CA1) fold greater deposition than in APPsw mice. There was no significant difference in neuronal counts in either CA1 or the frontal cortex between nontransgenic (non-tg), PS1 transgenic, APPsw, and PSAPP mice at 3 to 12 months of age. In the PSAPP mice, there was disorganization of the neuronal architecture by compact amyloid plaques, and the average number of neurons was 8 to 10% fewer than the other groups (NS, P > 0.10) in CA1 and 2 to 20% fewer in frontal cortex (NS, P = 0.31). There was no loss of total synaptophysin immunoreactivity in the Fc or dentate gyrus molecular layer of the 12-month-old PSAPP mice. Thus, although co-expression of mutant PS1 with Swedish mutant betaAPP leads to marked cortical and limbic Abeta deposition in an age-dependent manner, it does not result in the dramatic neuronal loss in hippocampus and association cortex characteristic of AD.     

Functional frontoparietal connectivity during short-term memory as revealed by high-resolution EEG coherence analysis

In this electroencephalographic study, the authors modeled the functional connectivity between frontal and parietal areas during short-term memory (STM) processes by spectral coherence analysis and the directed transfer function, that is, for the estimation of coherence "direction." A no-STM task was used as a reference. STM was characterized by an increased frontoparietal electroencephalograph coherence at high frequencies (beta and gamma, 14-45 Hz). In the control task, parietal-to-frontal flow prevailed at those frequencies. However, the STM task showed a bidirectional frontoparietal flow at the gamma band. In conclusion, frontoparietal connectivity would optimize "representational" memory during STM. In this context, the frontal areas would increase their influence on parietal areas for memory retention.     

Water-soluble chitosan inhibits the production of pro-inflammatory cytokine in human astrocytoma cells activated by amyloid beta peptide and interleukin-1beta

A chronic inflammatory response associated with beta-amyloid (Abeta) and interleukin-1beta (IL-1beta) is responsible for the pathology of Alzheimer's disease (AD). Astrocytes are predominant neuroglial cells of the central nervous system and are actively involved in cytokine-mediated events in AD. To investigate the biological effect of water-soluble chitosan (WSC), we examined cytotoxicity, production of pro-inflammatory cytokines and inducible nitric-oxide synthase (iNOS) on human astrocytoma cell line CCF-STTG1 stimulated with IL-1beta and Abeta fragment 25-35 (Abeta[25-35]). In 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide colorimetric assay, WSC by itself had no effect on cell viability on human astrocytoma cells. The effects of WSC on tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were evaluated with enzyme-linked immunosorbent assay and Western blotting. The production of TNF-alpha and IL-6 was induced by IL-1beta and Abeta[25-35] and synergistically amplified by the co-stimulation of IL-1beta and Abeta[25-35]. The secretion and expression of pro-inflammatory cytokines, TNF-alpha and IL-6, was significantly inhibited by pretreatment with WSC in human astrocytoma cells. The expression of iNOS was induced by IL-1beta and Abeta[25-35] and was partially inhibited by treatment with WSC. We demonstrate the regulatory effects of WSC in human astrocytes for the first time and suggest the anti-inflammatory effect of WSC may reduce and delay AD pathologic events.     

A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25-35

By means of i.c.v. administration of preaggregated oligomeric beta-amyloid (Abeta)25-35 peptide it was possible in rats to generate neuropathological signs related to those of early stages of Alzheimer's disease (AD). Abeta25-35-administration induced the deposition of endogenously produced amyloid protein. Furthermore, quantitative immunohistochemistry demonstrated time-related statistically significant increases in amyloid immunoreactivity, tau phosphorylation, microglial activation, and astrocytosis, and stereological investigations demonstrated statistically significant increased neuronal cell death and brain atrophy in response to Abeta25-35. Finally, the Abeta25-35-administration led to a reduced short-term memory as determined by the social recognition test. A synthetic peptide termed FGL derived from the neural cell adhesion molecule (NCAM) was able to prevent or, if already manifest, strongly reduce all investigated signs of Abeta25-35-induced neuropathology and cognitive impairment. The FGL peptide was recently demonstrated to be able to cross the blood-brain-barrier. Accordingly, we found that the beneficial effects of FGL were achieved not only by intracisternal, but also by intranasal and s.c. administration of the peptide. Furthermore, FGL-treatment was shown to inhibit the activity of GSK3beta, a kinase implicated in signaling regulating cell survival, tau phosphorylation and the processing of the amyloid precursor protein (APP). Thus, the peptide induced a statistically significant increase in the fraction of GSK3beta phosphorylated on the Ser9-position, a posttranslational modification known to inhibit the activity of the kinase. Hence, the mode of action of FGL with respect to the preventive and curative effects on Abeta25-35-induced neuropathological manifestations and cognitive impairment involves the modulation of intracellular signal-transduction mediated through GSK3beta.     

The prion protein in human neurodegenerative disorders

The binding sites of nicotinic acetylcholine receptor (nAChR) subtypes were measured in the parietal cortex and hippocampus of transgenic mice carrying mutant human APPswe and presenilin 1 (PS1) genes (APPswe/PS1 mice) between the ages of 3 weeks and 17 months. Soluble and insoluble beta-amyloid peptide (Abeta1-40 and Abeta1-42) levels were investigated in parallel. No significant differences in binding sites of [(3)H]cytisine (alpha4beta2 nAChRs) and [(125)I]alpha-bungarotoxin (alpha7 nAChRs) were observed in APPswe/PS1 mice and wild-type control mice at any age studied. At three weeks of age, soluble Abeta1-40 was detectable in the parietal cortex and hippocampus of APPswe/PS1 mice, whereas Abeta1-42 was detectable from 12 months of age. A pronounced increase in insoluble Abeta1-42 was observed between 3 weeks and 17 months compared with that of insoluble Abeta1-40 in both brain regions, indicating a shift that favors accumulation of Abeta1-42 in older APPswe/PS1 mice. The findings indicate that elevated Abeta levels in the brains of APPswe/PS1 mice do not alter the number of alpha4beta2 and alpha7 receptors, the two major brain nAChR subtypes.     

Chronic stimulation of GABAA receptor with muscimol reduces amyloid beta protein (25-35)-induced neurotoxicity in cultured rat cortical cells

The present study was performed to examine how the stimulation of gamma-aminobutyric acid (GABA) receptor affects amyloid beta protein (25-35) (Abeta (25-35)), a synthetic 25-35 amyloid peptide, -induced neurotoxicity using cultured rat cortical neurons. Abeta (25-35) produced a concentration-dependent reduction of cell viability, which was significantly reduced by (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801), an N-methyl-d-aspartate (NMDA) receptor antagonist, verapamil, an L-type Ca(2+) channel blocker, and N(G)-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor. Pretreatment with muscimol, a GABAA receptor agonist, over a concentration range of 0.1-10microM 24h before the treatment with 10microM Abeta (25-35) showed concentration-dependent inhibition on the Abeta (25-35)-induced neuronal apoptotic death. However, baclofen (1 and 10microM), a GABAB receptor agonist, failed to inhibit the Abeta (25-35)-induced neuronal death. In addition, pretreatment with muscimol (1microM) for 24h inhibited the Abeta (25-35) (10microM)-induced elevation of cytosolic Ca(2+) concentration ([Ca(2+)]c) and glutamate release, generation of reactive oxygen species (ROS), and caspase-3 activity in cultured neurons. These neuroprotective effects of muscimol (1microM) were completely blocked by the simultaneous treatment with 10microM bicuculline, a GABAA receptor antagonist, indicating that the protective effects of muscimol were due to GABAA receptor stimulation. When, however, treated just 15min before the treatment with Abeta (25-35), muscimol (1microM) did not show any protective effect against Abeta (25-35) (10microM)-induced neurotoxicity in cultured neurons. These results suggest that the chronic activation of GABAA receptor may ameliorate Abeta-induced neurotoxicity by interfering with the increase of [Ca(2+)]c, and then by inhibiting glutamate release, generation of ROS and caspase-3 activity.     

Blockade of long-term potentiation by beta-amyloid peptides in the CA1 region of the rat hippocampus in vivo

The effect of intracerebroventricular (icv) injections of beta-amyloid peptide fragments Abeta[15-25], Abeta[25-35], and Abeta[35-25] were examined on synaptic transmission and long-term potentiation (LTP) in the hippocampal CA1 region in vivo. Rats were anesthetized using urethan, and changes in synaptic efficacy were determined from the slope of the excitatory postsynaptic potential (EPSP). Baseline synaptic responses were monitored for 30 min prior to icv injection of Abeta peptides or vehicle. High-frequency stimulation (HFS) to induce LTP was applied to the Schaffer-collateral pathway 5 min or 1 h following the icv injection. HFS comprised 3 episodes of 10 stimuli at 200 Hz, 10 times, applied at 30-s intervals. Normal LTP measured 30 min following HFS, was produced following icv injection of vehicle (191 +/- 17%, mean +/- SE, n = 6) or Abeta[15-25; 100 nmol] (177 +/- 6%, n = 6) 1 h prior to HFS. LTP was, however, markedly reduced by Abeta[25-35; 10 nmol] (129 +/- 9%, n = 6, P < 0.001) and blocked by Abeta[25-35; 100 nmol] (99 +/- 6%, n = 6, P < 0.001). Injection of the reverse peptide, Abeta[35-25], also impaired LTP at concentrations of 10 nmol (136 +/- 3%, n = 6, P < 0.01) and 100 nmol (144 +/- 7, n = 8, P < 0.05). Using a different protocol, HFS was delivered 5 min following Abeta injections, and LTP was measured 1 h post HFS. Stable LTP was produced in the control group (188 +/- 15%, n = 7) and blocked by Abeta[25-35, 100 nmol] (108 +/- 15%, n = 6, P < 0.001). A lower dose of Abeta[25-35; 10 nmol] did not significantly impair LTP (176 +/- 30%, n = 4). The Abeta-peptides tested were also shown to have no significant effect on paired pulse facilitation (interstimulus interval of 50 ms), suggesting that neither presynaptic transmitter release or activity of interneurons in vivo are affected. The effects of Abeta on LTP are therefore likely to be mediated via a postsynaptic mechanism. This in vivo model of LTP is extremely sensitive to Abeta-peptides that can impair LTP in a time- ([25-35]) and concentration-dependent manner ([25-35] and [35-25]). These effects of Abeta-peptides may then contribute to the cognitive deficits associated with Alzheimer's disease.     

Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide

Acetylcholinesterase (AChE) activity is increased within and around amyloid plaques, which are present in Alzheimer's disease (AD) patient's brain. In this study, using cultured retinal cells as a neuronal model, we analyzed the effect of the synthetic peptide Abeta(25-35) on the activity of AChE, the degradation enzyme of acetylcholine, as well as the involvement of oxidative stress in this process. The activity of AChE was increased when retinal cells were incubated with Abeta(25-35) (25 microM, 24 h) and antioxidants such as alpha-tocopherol acetate and nitric oxide synthase (NOS) inhibitors were capable of preventing this effect. Despite Abeta(25-35) did not affect cell membrane integrity, the redox capacity of cells decreased. The incubation with this amyloidogenic peptide led to an increment of reactive oxygen species formation (20%), of lipid peroxidation (65%), and basal intracellular calcium levels (40%). The data obtained show that the enhancement of AChE activity induced by Abeta(25-35) is mediated by oxidative stress, and that vitamin E and NOS inhibitors, by preventing the compromise of the enzyme activity, can have an important role in the maintenance of acetylcholine synaptic levels, thus preventing or improving cognitive and memory functions of AD patients.     

Effects of beta-amyloid protein on serotoninergic, noradrenergic, and cholinergic markers in neurons of the pontomesencephalic tegmentum in the rat

The effects on serotoninergic, noradrenergic and cholinergic markers on neurons of the pontomesencephalic tegmentum nuclei were studied in rats following local administration of fibrillar beta-amyloid peptide (Abeta1-40) into the left retrosplenial cortex. Focal deposition of Abeta in the retrosplenial cortex resulted in a loss of serotoninergic neurons in the dorsal and median raphe nuclei. The dorsal raphe nucleus showed a statistically significant reduction of 31.7% in the number of serotoninergic neurons and a decrease (up to 17.38%) in neuronal density in comparison with the same parameters in uninjected controls. A statistically significant reduction of 50.3%, together with a significant decrease of 53.94% in the density of serotoninergic neurons, was also observed in the median raphe nucleus as compared with control animals. Furthermore, a significant reduction of 35.07% in the number of noradrenergic neurons as well as a statistically significant decrease of 56.55% in the density of dopamine-beta-hydroxylase-immunoreactive neurons were also found in the locus coeruleus as compared with the corresponding hemisphere in uninjected controls. By contrast, a reduction of 24.37% in the number of choline acetyltransferase-positive neurons and a slight decrease (up to 22.28%) in the density of cholinergic neurons, which were not statistically significant, was observed in the laterodorsal tegmental nucleus in comparison with the same parameters in control animals. These results show that three different neurochemically defined populations of neurons in the pontomesencephalic tegmentum are affected by the neurotoxicity of Abeta in vivo and that Abeta might indirectly affect serotoninergic, noradrenergic and cholinergic innervation in the retrosplenial cortex.     

Evidence for a frontoparietal control system revealed by intrinsic functional connectivity

Two functionally distinct, and potentially competing, brain networks have been recently identified that can be broadly distinguished by their contrasting roles in attention to the external world versus internally directed mentation involving long-term memory. At the core of these two networks are the dorsal attention system and the hippocampal-cortical memory system, a component of the brain's default network. Here spontaneous blood-oxygenation-level-dependent (BOLD) signal correlations were used in three separate functional magnetic resonance imaging data sets (n = 105) to define a third system, the frontoparietal control system, which is spatially interposed between these two previously defined systems. The frontoparietal control system includes many regions identified as supporting cognitive control and decision-making processes including lateral prefrontal cortex, anterior cingulate cortex, and inferior parietal lobule. Detailed analysis of frontal and parietal cortex, including use of high-resolution data, revealed clear evidence for contiguous but distinct regions: in general, the regions associated with the frontoparietal control system are situated between components of the dorsal attention and hippocampal-cortical memory systems. The frontoparietal control system is therefore anatomically positioned to integrate information from these two opposing brain systems.     

Protective effects of Abeta-derived tripeptide, Abeta(32-34), on Abeta(1-42)-induced phosphatidylinositol 4-kinase inhibition and neurotoxicity

We previously reported that the neurotoxicity of pathophysiological concentrations of amyloid beta proteins (Abetas, 0.1-10nM) as assessed by the inhibition of type II phosphatidylinositol 4-kinase (PI4KII) activity and the enhancement of glutamate toxicity was blocked by a short fragment of Abeta, Abeta(31-35). Such protective effects of shorter fragments derived from Abeta(31-35) were examined in this study to reach the shortest effective peptide, using recombinant human PI4KII and primary cultured rat hippocampal neurons. Among the peptides tested (Abeta(31-34), Abeta(31-33), Abeta(31-32), Abeta(32-35), Abeta(33-35), Abeta(34-35), Abeta(32-34), Abeta(33-34) and Abeta(32-33)), Abeta(31-34), Abeta(32-35) and Abeta(32-34) blocked both the Abeta(1-42)-induced inhibition of PI4KII activity and enhancement of glutamate toxicity on cell viability. The shortest peptide among them, Abeta(32-34), showed a dose-dependent protective effect with 50% effective concentration near 1nM, while Abeta(34-32), with a reverse amino acid sequence for Abeta(32-34), showed no protective effects. Thus, a tripeptide, Abeta(32-34) i.e. Ile-Gly-Leu, may be available as a lead compound for designing effective Abeta antagonists.     

Effects of gonadal hormone replacement on measures of basal forebrain cholinergic function

The effects of different hormone replacement regimens on basal forebrain cholinergic function were examined by measuring changes in choline acetyltransferase activity and high affinity choline uptake in adult, ovariectomized, rats. Increases in choline acetyltransferase activity were detected in the frontal cortex (20. 1%) and olfactory bulbs (30.4%) following two weeks, but not four weeks, of repeated treatment with estrogen plus progesterone. Increases in high affinity choline uptake were detected in the frontal cortex (39.5-55.1%), hippocampus (34.9-48.9%), and olfactory bulbs (29.9%) after two weeks, but not four weeks, of either continuous estrogen administration, repeated progesterone administration, or repeated treatment with estrogen plus progesterone. Repeated administration of estradiol (2-25 microg/250 g body weight) for two or four weeks, and continuous estrogen administration for four weeks and six months, produced no significant changes in choline acetyltransferase activity or high affinity choline uptake in the hippocampus, frontal cortex or olfactory bulbs. Continuous estrogen administration for 13 months produced a significant decrease in high affinity choline uptake across all regions with the largest effect (-28.1%) detected in the hippocampus.The findings demonstrate that short-term treatment with estrogen and/or progesterone can significantly enhance cholinergic function within specific targets of the basal forebrain cholinergic projections. Most important is the fact that the effects varied considerably according to the manner and regimen of hormone replacement and did not persist with prolonged treatment. These findings could have important implications for the effective use of hormone replacement strategies in the prevention and treatment of Alzheimer's disease and age-related cognitive decline in women.     

Negative association between amyloid plaques and cerebral amyloid angiopathy in Alzheimer's disease

Cerebral amyloid angiopathy (CAA) is an important, though still relatively neglected, aspect of the pathology of Alzheimer's disease (AD), and both the source of amyloid beta protein (Abeta) in CAA, and its relationship to senile plaque (SP) Abeta, remain unclear. We have investigated the relationship between Abeta deposition in SP and CAA in four regions of brain from 69 patients with AD in order to gain insight into the pathogenetic mechanism(s) underlying these pathologies. CAA was present to some degree in all 69 patients, with the occipital cortex being affected more often and more severely than frontal, temporal and parietal cortices. By definition, SPs were present in all brain areas in all 69 patients, with greater uniformity of distribution than CAA, though the occipital cortex was less severely affected than the other brain regions. There was no significant (positive) correlation between CAA rating and that of SP for any one cortical region, but on combining data from all four regions there was a significant inverse correlation (P=0.037) between CAA and SP ratings. Such data suggest that the cellular sources and mechanisms leading to Abeta deposition as SP or CAA are likely to differ and may proceed independently of each other.