Abeta Peptide~Beta Amyloid

1. Phytother Res. 2010 Oct;24(10):1538-42.

Neuroprotective effect of honokiol and magnolol, compounds from Magnolia
officinalis, on beta-amyloid-induced toxicity in PC12 cells.

Hoi CP, Ho YP, Baum L, Chow AH.

School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong,
China.

Amyloid β peptide (Aβ) induced toxicity is a well-established pathway of neuronal
cell death which might play a role in Alzheimer's disease. In this regard, the
toxic effect of Aβ on a cultured Aβ-sensitive neuronal cell line was used as a
primary screening tool for potential anti-Alzheimer's therapeutic agents. The
effects of nine pure compounds (vitamin E, α-asarone, salidroside, baicolin,
magnolol, gastrodin, bilobalide, honokiol and β-asarone) from selected Chinese
herbs on neuronal cell death induced by Aβ in NGF-differentiated PC12 cells were
examined. Only two of the studied compounds, honokiol and magnolol, significantly
decreased Aβ-induced cell death. Further experiments indicated that their
neuroprotective effects are possibly mediated through reduced ROS production as
well as suppression of intracellular calcium elevation and inhibition of
caspase-3 activity. The results provide for the first time a scientific rationale
for the clinical use of honokiol and magnolol in the treatment of Alzheimer's
disease. Copyright © 2010 John Wiley & Sons, Ltd.


PMID: 20878707 [PubMed - in process]


2. J Biol Chem. 2010 Sep 28. [Epub ahead of print]

Statins promote the degradation of extracellular amyloid {beta}-peptide by
microglia via stimulation of exosome-associated IDE secretion.

Tamboli IY, Barth E, Christian L, Siepmann M, Singh S, Tolksdorf K, Heneka MT,
Luetjohann D, Wunderlich P, Walter J.

University Hospital Bonn, Germany;

Epidemiological studies indicate that intake of statins decrease the risk of
developing Alzheimer's disease (AD). Cellular and in vivo studies suggested that
statins might decrease the generation of the amyloid β-peptide (Aβ) from the
β-amyloid precursor protein (APP). Here, we show that statins potently stimulate
the degradation of extracellular Aβ by microglia. The statin-dependent clearance
of extracellular Aβ is mainly exerted by insulin degrading enzyme (IDE) which is
secreted in a non-conventional pathway in association with exosomes. Stimulated
IDE secretion and Aβ degradation was also observed in blood of mice upon
peripheral treatment with lovastatin. Importantly, increased IDE secretion upon
lovastatin treatment was dependent on protein isoprenylation and upregulation of
exosome secretion by fusion of multivesicular bodies (MVBs) with the plasma
membrane. These data demonstrate a novel pathway for the non-conventional
secretion of IDE via exosomes. The modulation of this pathway could provide a new
strategy to enhance the extracellular clearance of Aβ.


PMID: 20876579 [PubMed - as supplied by publisher]


3. Neuroscience. 2010 Sep 25. [Epub ahead of print]

Cloning, sequencing and expression in the dog of the main APP isoforms and some
of the enzymes related with their processing.

Sarasa L, Gallego C, Monleón I, Olvera A, Canudas J, Montañés M, Pesini P, Sarasa
M.

Montecanal Laboratory, Araclon Biotech, Zaragoza, Spain.

Alzheimer's disease (AD) is characterized by neuronal loss and the presence of
both neurofibrillary tangles and senile plaques in the brain. These plaques arise
from the deposition of beta-amyloid (Aβ) peptides (38-43 amino acids), which are
generated from enzymatic cleavage of the amyloid precursor protein (APP) by β-
and γ- secretases. In the present work, we cloned the principal APP isoforms as
well as some enzymes that have been implicated in their amyloidogenic and
non-amyloidogenic processing in dogs. Additionally, the main proteases implicated
in the degradation of Aβ were also studied. We also investigated the level of
expression of these APP isoforms and enzymes in different brain regions and in
peripheral tissues. Our data demonstrate that these canine proteins are highly
homologous to their human counterparts. In addition, the expression pattern of
these proteins in dogs is consistent with previous data reported in humans. Thus,
dogs may be a natural model to study the biology of AD and could also serve as an
animal model for Aβ-targeted drugs against this devastating disease.


PMID: 20875843 [PubMed - as supplied by publisher]


4. Brain Res. 2010 Sep 25. [Epub ahead of print]

Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in
Alzheimer's disease.

Thorsell A, Bjerke M, Gobom J, Brunhage E, Vanmechelen E, Andreasen N, Hansson O,
Minthon L, Zetterberg H, Blennow K.

Institute of Neuroscience and Physiology, Department of Psychiatry and
Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal,
Sweden.

Synaptic pathology occurs early in Alzheimer's disease (AD) development, and
cerebrospinal fluid biomarkers for synaptic damage may be altered early in the
disease process. In the present study we examined cerebrospinal fluid levels of
the postsynaptic protein neurogranin in patients with mild cognitive impairment
(MCI) or AD and controls. The low neurogranin level in cerebrospinal fluid
required enrichment by immunoprecipitation prior to mass spectrometric
identification and semi-quantitative immunoblot analysis. Relative quantification
revealed a significant increase of neurogranin in the AD group compared with
controls, while the MCI group was not statistically different from either
controls or the AD group. The concentration of the AD biomarkers T-tau,
P-tau(181) and Aβ(42) were significantly changed in the control and MCI groups
compared with the AD group, but no significant differences were found between the
MCI group and controls for the three biomarkers. Nevertheless, a trend towards
increasing levels of neurogranin, T-tau and P-tau(181) was found in cerebrospinal
fluid from MCI patients compared with controls. The elevated neurogranin levels
in the MCI and AD groups might reflect synaptic degeneration. These results
together suggest that cerebrospinal fluid neurogranin might be valuable together
with the established AD biomarkers in the early diagnosis of AD and warrants
further studies to determine the diagnostic value of neurogranin.


PMID: 20875798 [PubMed - as supplied by publisher]


5. J Am Chem Soc. 2010 Sep 28. [Epub ahead of print]

Combination of Kinetically Selected Inhibitors in Trans Leads to Highly Effective
Inhibition of Amyloid Formation.

Meng F, Raleigh DP, Abedini A.

Department of Chemistry, State University of New York at Stony Brook, Stony
Brook, New York 11794-3400, and Department of Medicine, New York University
Medical Center, 550 First Avenue, New York, New York 10016.

Amyloid formation plays a role in over 25 human disorders. A range of strategies
have been applied to the problem of developing inhibitors of amyloid formation,
but unfortunately, many inhibitors are effective only in molar excess and
typically either lengthen the time to the onset of amyloid formation, (the lag
time), while having modest effects on the total amount of amyloid fibrils
produced, or decrease the amount of amyloid without significantly reducing the
lag time. We demonstrate a general strategy whereby two moderate inhibitors of
amyloid formation can be rationally selected via kinetic assays and combined in
trans to yield a highly effective inhibitor which dramatically delays the time to
the appearance of amyloid and drastically reduces the total amount of amyloid
formed. A key feature is that the selection of the components of the mixture is
based on their effect on the time course of amyloid formation rather than on just
the amount of amyloid produced. The approach is validated using inhibitors of
amyloid formation by islet amyloid polypeptide, the causative agent of amyloid
formation in type 2 diabetes and the Alzheimer's disease Aβ peptide.


PMID: 20873820 [PubMed - as supplied by publisher]


6. Zhong Yao Cai. 2010 May;33(5):763-7.

[The protective effect of puerarin on Abeta(25-35)-induced PC12 cell injury]

[Article in Chinese]

Zhang HY, Yi XN, Liu YH, Lao ML, Zhang XF.

Department of Anatomy, Hainan Medical College, Haikou 571101, China.
hyzhang_xjtu@yahoo.cn

OBJECTIVE: To study The protective effect of puerarin on Abeta(25-35)-induced
PC12 cell injury. METHODS: PC12 cells were treated with puerarin for 0.5 h, then
incubated with Abeta(25-35) (50 micromol/L) for 24 h to investigate the
production of reactive oxygen species (ROS), mitochondrial membrane potential
levels and Caspase-3 activation; The expressions of Bax, bcl-2 were measured by
Western Blotting. RESULTS: Preincubation of the cell with puerarin could inhibit
the ROS and increase mitochondrial membrane potential levels. Puerarin was also
found to increase the Bcl-2/Bax ratio and reduce Caspase-3 activation.
CONCLUSION: Puerarin may act as an intracellular ROS scavenger, and its
antioxidant properties may protect against Abeta(25-35)-induced cell injury.


PMID: 20873562 [PubMed - in process]


7. Biopolymers. 2010 Sep 24. [Epub ahead of print]

CD measurements of β-amyloid (1-40) and (1-42) in the condensed phase.

Harada T, Kuroda R.

Japan Science and Technology Agency, ERATO-SORST Kuroda Chiromorphology Team,
4-7-6 Komaba, Meguro-ku, Tokyo, 153-0041, Japan.

Circular Dichroism (CD) spectroscopy of proteins/peptides in thin films can
provide valuable information on the structures in the aggregated states, however,
it is difficult to estimate the secondary structure content quantitatively due to
artifact signals arising from macroscopic anisotropies which is unique to the
solid phase. Using a Universal Chiroptical Spectrophotometer (UCS-1) together
with the measurement and analytical procedures we have developed, we could obtain
artifact-free CD spectra of cast and Langmuir-Blodgett (L-B) films of synthetic
peptides, Aβ (1-40) and (1-42) which are related to Alzheimer's disease. The work
gave insights into the mechanisms for structural transformation and amyloid-like
aggregation. © 2010 Wiley Periodicals, Inc. Biopolymers, 2010.


PMID: 20872872 [PubMed - as supplied by publisher]


8.  Error occurred:
PMID: 20870845

9. Int J Alzheimers Dis. 2010 Aug 12;2010. pii: 723782.

Neuron loss in transgenic mouse models of Alzheimer's disease.

Wirths O, Bayer TA.

Division of Molecular Psychiatry and Alzheimer Ph.D. Graduate School, Department
of Psychiatry, University of Goettingen, von-Siebold-Str. 5, 37075 Goettingen,
Germany.

Since their initial generation in the mid 1990s, transgenic mouse models of
Alzheimers's disease (AD) have been proven to be valuable model systems which are
indispensable for modern AD research. Whereas most of these models are
characterized by extensive amyloid plaque pathology, inflammatory changes and
often behavioral deficits, modeling of neuron loss was much less successful. The
present paper discusses the current achievements of modeling neuron loss in
transgenic mouse models based on APP/Aβ and Tau overexpression and provides an
overview of currently available AD mouse models showing these pathological
alterations.


PMCID: PMC2943100
PMID: 20871861 [PubMed - in process]


10. Free Radic Biol Med. 2010 Sep 22. [Epub ahead of print]

Oxidative Modification to LDL-related Receptor Protein 1 (LRP1) in Hippocampus
from Subjects with Alzheimer's Disease: Implications for Aβ Accumulation in AD
Brain.

Owen JB, Sultana R, Aluise CD, Erickson MA, Price TO, Bu G, Banks WA, Butterfield
DA.

Department of Chemistry, University of Kentucky, Lexington KY 40506-0055; Center
of Membrane Sciences, University of Kentucky, Lexington, KY 40506-0059, USA.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized
histopathologically by the presence of senile plaques (SP), neurofibrillary
tangles, and synapse loss. The main component of SP is amyloid-β peptide (Aβ)
that has been associated with increased oxidative stress, leading to oxidative
modification of proteins and consequently to neurotoxicity and neurodegeneration.
Low-density lipoprotein receptor-related protein 1 (LRP1) is the primary moiety
responsible for the efflux of Aβ from the brain to the blood across the
blood-brain barrier (BBB). Impaired brain-to-blood transport of Aβ by LRP1 has
been hypothesized to contribute to increased levels of Aβ in AD brain. The cause
of LRP1 dysfunction is unknown, but we have hypothesized that Aβ oxidizes LRP1,
thus damaging its own transporter. Consistent with this notion, we report in the
current study a significant increase in the levels of the lipid peroxidation
product 4-hydroxy-2-nonenal (HNE) bound to transmembrane LRP1 in AD hippocampus.
In contrast, the levels of LRP1-resident 3-nitrotyrosine (3NT) did not show a
significant increase in AD hippocampus compared to age-matched controls. Based on
this study, we propose that Aβ impairs its own efflux from the brain by oxidation
of its transporter LRP1, leading to increased Aβ deposition in brain, thereby
contributing to subsequent cognitive impairment in AD.


PMID: 20869432 [PubMed - as supplied by publisher]


11. Neurosci Lett. 2010 Sep 22. [Epub ahead of print]

Cholinesterase Inhibitor use is associated with increased plasma levels of
anti-Abeta 1-42 antibodies in Alzheimer's Disease patients.

Conti E, Galimberti G, Tremolizzo L, Masetto A, Cereda D, Zanchi C, Piazza F,
Casati M, Isella V, Appollonio I, Ferrarese C.

Department of Neuroscience and Biomedical Technologies, University of
Milano-Bicocca, San Gerardo Hospital, Monza (MI), Italy.

Acetyl-cholinesterase inhibitors (AChEI) are drugs frequently prescribed for the
treatment of Alzheimer's disease (AD), exerting an effect on cognition, as well
as on behavioural and psychological symptoms of dementia and activities of daily
living. The efficacy of AChEI may be ascribed not only to the activation of
cholinergic transmission, but also to other mechanisms, among which a putative
regulation of the immune response has already been hypothesized. In the present
study, we evaluated, in a cross-sectional sample of 66 AD patients and 48 healthy
controls, the putative influence of AChEI on anti-Abeta 1-42 antibody plasma
levels by ELISA assay. AD patients receiving AChEI therapy showed increased
plasma levels of anti-Abeta 1-42 antibodies respect to untreated AD patients and
antibodies levels similar to those of healthy controls, both before and after
normalization by total IgG values. Our results support a potential role of AChEI
in the modulation of the immune response against Abeta. We suggest that a
strategy aimed at increasing the endogenous response against this peptide might
represent an interesting therapeutic target to be further investigated.


PMID: 20869427 [PubMed - as supplied by publisher]


12. Biochimie. 2010 Sep 21. [Epub ahead of print]

Targeting cyclooxygenases-1 and -2 in neuroinflammation: Therapeutic
implications.

Aïd S, Bosetti F.

Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National
Institute on Aging, NIH, Bethesda, MD 20892.

Neuroinflammation has been implicated in the pathogenesis or the progression of a
variety of acute and chronic neurological and neurodegenerative disorders,
including Alzheimer's disease. Prostaglandin H synthases or cyclooxygenases (COX
-1 and COX-2) play a central role in the inflammatory cascade by converting
arachidonic acid into bioactive prostanoids. In this review, we highlighted
recent experimental data that challenge the classical view that the inducible
isoform COX-2 is the most appropriate target to treat neuroinflammation. First,
we discussed data showing that COX-2 activity is linked to anti-inflammatory and
neuroprotective actions and is involved in the generation of novel lipid
mediators with pro-resolution properties. Then, we reviewed recent data
demonstrating that COX-1, classically viewed as the homeostatic isoform, is
actively involved in brain injury induced by pro-inflammatory stimuli including
Aβ, lipopolysaccharide, IL-1β, and TNF-α. Overall, we suggest revisiting the
traditional views on the roles of each COX during neuroinflammation and we
propose COX-1 inhibition as a viable therapeutic approach to treat CNS diseases
with a marked inflammatory component.


PMID: 20868723 [PubMed - as supplied by publisher]


13. Eur J Pharmacol. 2010 Sep 21. [Epub ahead of print]

Puerarin attenuates amyloid-beta-induced cognitive impairment through suppression
of apoptosis in rat hippocampus in vivo.

Li J, Wang G, Liu J, Zhou L, Dong M, Wang R, Li X, Li X, Lin C, Niu Y.

Elevated levels of β-amyloid (Aβ) in the brains being a hallmark of Alzheimer's
disease have been believed to play a critical role in the cognitive dysfunction
that occurs in Alzheimer's disease. Recent evidence suggests that Aβ induces
neuronal apoptosis in the brain and in primary neuronal cultures. In this study,
we investigated the effects of puerarin, a phytoestrogen isolated from Pueraria
lobata, on cognitive function and neuronal apoptosis in the intrahippocampal
injection of Aβ rats and its mechanism of action. The results show the
intrahippocampal injection of Aβ induced a spatial memory deficit, apoptosis, and
caspase-9 activation in hippocampal neurons. Puerarin treatment ameliorated
Aβ(1-42)-induced cognitive impairment and reversed the increase of apoptosis in
the hippocampus. The attenuation is associated with the activation of Akt and
phosphorylation of Bad. These results suggest that puerarin may be an
anti-Alzheimer's disease candidate drug to suppress both Alzheimer's
disease-related neuronal cell apoptosis and dysfunction of the memory system.


PMID: 20868658 [PubMed - as supplied by publisher]


14. Hippocampus. 2010 Apr 13. [Epub ahead of print]

Chronic psychosocial stress accelerates impairment of long-term memory and
late-phase long-term potentiation in an at-risk model of Alzheimer's disease.

Tran TT, Srivareerat M, Alkadhi KA.

Department of Pharmacological and Pharmaceutical Sciences, University of Houston,
College of Pharmacy, Houston, Texas.

Although it is generally agreed that Aβ contributes to the pathogenesis of AD,
its precise role in AD and the reason for the varying intensity and time of onset
of the disease have not been elucidated. In addition to genetic factors,
environmental issues such as stress may also play a critical role in the etiology
of AD. This study examined the effect of chronic psychosocial stress in an
at-risk (treatment with a subpathogenic dose of Aβ; "subAβ") rat model of AD on
long-term memory by three techniques: memory tests in the radial arm water maze,
electrophysiological recordings of synaptic plasticity in anesthetized rats, and
immunoblot analysis of learning- and long-term memory-related signaling
molecules. Chronic psychosocial stress was induced using a rat intruder model.
The subAβ rat model of AD was induced by continuous infusion of 160 pmol/day
Aβ(1-42) via a 14-day i.c.v. osmotic pump. All tests showed that subAβ rats were
not different from control rats. Result from behavioral tests and
electrophysiological recordings showed that infusion of subAβ in chronically
stressed rats (stress/subAβ group) caused significant impairment of cognitive
functions and late-phase long-term potentiation (L-LTP). Molecular analysis of
various signaling molecules after expression of L-LTP, revealed an increase in
the levels of p-CREB in control, stress, and subAβ rats, but not in the
stress/subAβ rats. These findings suggest that the chronic stress-induced
molecular alteration may accelerate the impairment of cognition and synaptic
plasticity in individuals "at-risk" for AD. © 2010 Wiley-Liss, Inc.


PMID: 20865724 [PubMed - as supplied by publisher]


15. Hum Vaccin. 2010 Nov 9;6(11). [Epub ahead of print]

Virus-like particle based vaccines for Alzheimer disease.

Chackerian B.

Department of Molecular Genetics and Microbiology, University of New Mexico
School of Medicine, Albuquerque, NM, USA. bchackerian@salud.unm.edu.

Vaccines targeting the amyloid-β (Aβ) peptide have promise as immunotherapies for
the treatment of Alzheimer disease (AD). Human trials of a first generation Aβ
vaccine highlighted the need for a vaccine strategy that could consistently
induce high-titer antibodies against Aβ without also inducing inflammatory
auto-reactive T cell responses. In this review, I will describe the use of
virus-like particle (VLP) based vaccines against Aβ that can potentially satisfy
these demands. VLPs can serve as highly multivalent platforms for the display of
diverse antigens on their surfaces. VLP display markedly increases the
immunogenicity of antigens, including self-antigens. VLP-based immunogens
targeting Ab have been developed by several different groups, and have
demonstrated effectiveness in animal models of AD. One VLP-based candidate
vaccine for AD, CAD106, developed by Cytos Biotechnology and Novartis
Pharmaceuticals, is currently in human clinical trials.


PMID: 20864801 [PubMed - as supplied by publisher]


16. Am J Pathol. 2010 Sep 23. [Epub ahead of print]

CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid
Deposition in Two Alzheimer's Disease Mouse Models.

Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, Lamb BT.

From the Department of Neurosciences, Lerner Research Institute,* The Cleveland
Clinic; and the Departments of Neurosciences, and Genetics, Case Western Reserve
University School of Medicine, Cleveland, Ohio.

Microglia, the primary immune effector cells in the brain, continually monitor
the tissue parenchyma for pathological alterations and become activated in
Alzheimer's disease. Loss of signaling between neurons and microglia via deletion
of the microglial receptor, CX3CR1, worsens phenotypes in various models of
neurodegenerative diseases. In contrast, CX3CR1 deficiency ameliorates pathology
in murine stroke models. To examine the role of CX3CR1 in Alzheimer's
disease-related β-amyloid pathology, we generated APPPS1 and R1.40 transgenic
mouse models of Alzheimer's disease deficient for CX3CR1. Surprisingly, CX3CR1
deficiency resulted in a gene dose-dependent reduction in β-amyloid deposition in
both the APPPS1 and R1.40 mouse models of AD. Immunohistochemical analysis
revealed reduced staining for CD68, a marker of microglial activation.
Furthermore, quantitative immunohistochemical analysis revealed reduced numbers
of microglia surrounding β-amyloid deposits in the CX3CR1-deficient APPPS1
animals. The reduced β-amyloid pathology correlated with reduced levels of TNFα
and CCL2 mRNAs, but elevated IL1β mRNA levels, suggesting an altered
neuroinflammatory milieu. Finally, to account for these seemingly disparate
results, both in vitro and in vivo studies provided evidence that CX3CL1/CX3CR1
signaling alters the phagocytic capacity of microglia, including the uptake of Aβ
fibrils. Taken together, these results demonstrate that loss of neuron-microglial
fractalkine signaling leads to reduced β-amyloid deposition in mouse models of AD
that is potentially mediated by altered activation and phagocytic capability of
CX3CR1-deficient microglia.


PMID: 20864679 [PubMed - as supplied by publisher]


17. J Biol Chem. 2010 Sep 23. [Epub ahead of print]

Macroautophagy is not directly involved in the metabolism of amyloid precursor
protein.

Boland B, Smith DA, Mooney D, Jung SS, Walsh DM, Platt FM.

University College Dublin, Ireland;

Alterations in the metabolism of amyloid precursor protein (APP) are believed to
play a central role in Alzheimers disease (AD) pathogenesis. Burgeoning data
indicates that APP is proteolytically processed in endosomal-autophagic-lysosomal
(EAL) compartments. In this study, we used both in vivo and in vitro paradigms to
determine if alterations in macroautophagy affect APP metabolism. Three mouse
models of glycosphingolipid (GSL) storage diseases, namely, Niemann Pick Type C1,
GM1 gangliosidosis and Sandhoff disease had mTOR-independent increases in the
autophagic vacuole (AV) associated protein, LC3-II, indicative of impaired
lysosomal flux. APP-C-terminal fragments (APP-CTFs) were also increased in brains
of the three mouse models, however, discrepancies between LC3-II and APP-CTFs
were seen between primary (GM1 gangliosidosis and Sandhoff disease) and secondary
(Niemann Pick Type C1) lysosomal storage models. APP-CTFs were proportionately
higher than LC3-II in cerebellar regions of GM1 gangliosidosis and Sandhoff
disease, while LC3-II increased before APP-CTFs in brains of NPC1 mice.
Endogenous murine Aβ40 from RIPA-soluble extracts was increased in brains of all
three mice. The in vivo relationship between AV and APP-CTF accumulation was also
seen in cultured neurons treated with agents that impair primary (chloroquine,
leupeptin + pepstatin) and secondary (U18666A, vinblastine) lysosomal flux.
However, Aβ secretion was unaffected by agents that induced autophagy (rapamycin)
or impaired AV clearance, and LC3-II positive AVs predominantly co-localised with
degradative LAMP-1-positive lysosomes. These data suggest that neuronal
macroautophagy does not directly regulate APP metabolism, but highlights the
important anti-amyloidogenic role of lysosomal proteolysis in post-secretase
APP-CTF catabolism.


PMID: 20864542 [PubMed - as supplied by publisher]


18. J Pharmacol Exp Ther. 2010 Sep 23. [Epub ahead of print]

H3 Receptor Miniseries: H3 Receptors and Pain Modulation: Peripheral, Spinal and
Brain Interactions.

Hough L, Rice FL.

1 Albany Medical College MC-136;

Histamine H(3) receptors (H(3)Rs), distributed within in the brain, the spinal
cord, and on specific types of primary sensory neurons, can modulate pain
transmission by several mechanisms. In the skin, H(3)Rs are found on certain Aβ
fibers, and on keratinocytes and Merkel cells, as well as on deep dermal,
peptidergic Aδ fibers terminating on deep dermal blood vessels. Activation of
H(3)Rs on the latter in the skin, heart, lung and dura mater reduces CGRP and
substance P release, leading to anti-inflammatory (but not antinociceptive)
actions. However, activation of H(3)Rs on the spinal terminals of these sensory
fibers reduces nociceptive responding to low intensity mechanical stimuli, and to
inflammatory stimuli such as formalin. These findings suggest that H(3)R agonists
might be useful analgesics, but these drugs have not been tested in
clinically-relevant pain models. Paradoxically, H(3) antagonists/ inverse
agonists have also been reported to attenuate several types of pain responses,
including phase II responses to formalin. In the periaquaductal gray (PAG, an
important pain regulatory center), the H(3) inverse agonist thioperamide releases
neuronal histamine and mimics histamine's biphasic modulatory effects in thermal
nociceptive tests. Newer H(3) inverse agonists with potent, selective, and
brain-penetrating properties show efficacy in several neuropathic and arthritis
pain models, but the sites and mechanisms for these actions remain poorly
understood.


PMID: 20864501 [PubMed - as supplied by publisher]


19. J Neuroimmunol. 2010 Sep 21. [Epub ahead of print]

Anti-11[E]-pyroglutamate-modified amyloid β antibodies cross-react with other
pathological Aβ species: Relevance for immunotherapy.

Perez-Garmendia R, Ibarra-Bracamontes V, Vasilevko V, Luna-Muñoz J, Mena R,
Govezensky T, Acero G, Manoutcharian K, Cribbs DH, Gevorkian G.

Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México
(UNAM), AP 70228, Cuidad Universitaria, México DF, 04510, Mexico.

N-truncated/modified forms of amyloid beta (Aß) peptide are found in diffused and
dense core plaques in Alzheimer's disease (AD) and Down's syndrome patients as
well as animal models of AD, and represent highly desirable therapeutic targets.
In the present study we have focused on N-truncated/modified Aβ peptide bearing
amino-terminal pyroglutamate at position 11 (AβN11(pE)). We identified two B-cell
epitopes recognized by rabbit anti-AβN11(pE) polyclonal antibodies.
Interestingly, rabbit anti-AβN11(pE) polyclonal antibodies bound also to
full-length Aβ1-42 and N-truncated/modified AβN3(pE), suggesting that the three
peptides may share a common B-cell epitope. Importantly, rabbit anti-AβN11(pE)
antibodies bound to naturally occurring Aβ aggregates present in brain samples
from AD patients. These results are potentially important for developing novel
immunogens for targeting N-truncated/modified Aβ aggregates as well, since the
most commonly used immunogens in the majority of vaccine studies have been shown
to induce antibodies that recognize the N-terminal immunodominant epitope (EFRH)
of the full length Aβ, which is absent in N-amino truncated peptides.


PMID: 20864186 [PubMed - as supplied by publisher]


20. J Neurol Sci. 2010 Sep 20. [Epub ahead of print]

Oxidative stress in Alzheimer's disease hippocampus: A topographical study.

Cruz-Sánchez FF, Gironès X, Ortega A, Alameda F, Lafuente JV.

Institute of Neurological and Gerontological Sciences, Faculty of Medicine,
International University of Catalonia, Josep Trueta, s/n. 08195 Sant Cugat del
Vallès, Barcelona, Spain.

Advanced glycation end-products (AGEs) and their receptor (RAGE) are molecules
related to oxidative stress demonstrated in aging and in several pathological
disorders including Alzheimer's disease (AD). Aging has been considered the main
risk factor for AD. Amyloid deposits (Aβ-D) and neurofibrillary tangles (NFT) are
pathological changes related to AD involving hippocampal regions. Different
degrees of AD pathology have been described according to distribution of NFTs in
different topographical regions of hippocampus and cerebral cortex. The
hippocampus shows a selective vulnerability under several noxes especially those
including hypoxia. Hypoxia in the nervous tissue induces oxidative stress. In an
attempt to find out more about anatomical distribution of the oxidative stress
through hippocampal regions in AD, a collection of brains were studied. Samples
from deceased patients who had suffered from AD and from age-matched controls
were immunohistochemically studied with AGE and RAGE antibodies according to a
topographical division of the hippocampus and brain cortical regions. Results
suggest that an oxidative stress pathway starts in the CA3 sector progresses to
CA1 and then continues to other hippocampal and cortical areas building a
pathoclitic pathway for Alzheimer's disease progression.


PMID: 20863531 [PubMed - as supplied by publisher]