Current Alzheimer Research (v.10, #3)

The drawbacks of amyloid immunotherapy, including the development of encephalitis, the lack of clinical improvementand of any effect on neurofibrillary tangles (NFTs), coupled with the central role of NFTs in dementia, maypoint that clearance of amyloid pathology is not sufficient for improving the dementia symptoms in Alzheimer

Multitarget Cannabinoids as Novel Strategy for Alzheimer Disease by Pedro Gonzalez-Naranjo, Nuria E. Campillo, Concepcion Perez, Juan A. Paez (229-239).
During the last years the development of approaches to multitarget drug design and discovery is gaining acceptance.The cannabinoids are potentially excellent multi-target drug candidates because of their interesting pharmacologicalprofiles, among which stands out the dual capacity of cannabinoid ligands to act as cannabinoid agonist and cholinesteraseinhibitors. In this article, inhibition, kinetics studies and docking simulations with a representative set of cannabinoids arepresented. The results of these studies showed the inhibitory capacity of some agonist cannabinoids with selectivity atAChE or BuChE enzymes. The kinetic and modelling studies allowed us to postulate the potential mode of action and thebinding site of the cannabinoids. In general, the studied cannabinoids showed a mixed type inhibition mode of action. Theexception to this behaviour was found for the agonist CP-55,940 that showed a non-competitive inhibition, suggesting thatthis cannabinoid only binds to the peripheral site.

The Safety, Tolerability, Pharmacokinetics and Cognitive Effects of GSK239512, a Selective Histamine H3 Receptor Antagonist in Patients with Mild to Moderate Alzheimer by Pradeep J. Nathan, Rebecca Boardley, Nicola Scott, Alienor Berges, Paul Maruff, Tharani Sivananthan, Neil Upton, Martin T. Lowy, Peter J. Nestor, Robert Lai (240-251).
Background: The histamine H<sub>3</sub> receptor plays a critical role in the negative neuromodulation of neurotransmittersinvolved in cognitive function. H<sub>3</sub> receptor antagonists/inverse agonists have been shown to exert pro-cognitive effectsin pre-clinical models. GSK239512 is a potent and selective H<sub>3</sub> receptor antagonist developed for the treatment ofcognitive dysfunction in neurodegenerative disorders. In this study we examined the safety, tolerability, pharmacokineticsand pro-cognitive effects of GSK239512 (oral) in patients with mild to moderate Alzheimer

Actions of the Anti-Angiogenic Compound Angiostatin in an Animal Model of Alzheimer by Jae K Ryu, Jonathan P Little, Andis Klegeris, Nattinee Jantaratnotai, James G McLarnon (252-260).
We have examined the anti-angiogenic compound, angiostatin as a modulator of inflammatory reactivity andvascular responses and for neuroprotection in an animal model of Alzheimer

Valproic Acid Attenuates Neuronal Loss in the Brain of APP/PS1 Double Transgenic Alzheimer by Zhimin Long, Min Zheng, Lei Zhao, Peng Xie, Cong Song, Yalan Chu, Weihong Song, Guiqiong He (261-269).
Alzheimer's disease (AD) is characterized by senile plaques (SP) of extracellular amyloid β peptides(Aβ), neurofibrillarytangles (NFT) of intracellular hyper-phosphorylated tau and widespread loss of neurons. Apoptosis is the mainreason of neuronal loss. It is proved that Aβ triggers apoptotic cell death via the activation of caspase-dependent and -independent cell death effectors, respectively. Valproic acid (VPA) is a widely used mood stabilizer and antiepilepticdrug. Our previous study showed that VPA treatment significantly reduced SP formation and improved memory deficitsin transgenic AD model mice. The present study intended to explore the protective effect of VPA on neuronal loss intransgenic AD model mice and the possible mechanisms involved. Histological and ultra-structural analysis showed thatVPA partially decreased the swollen mitochondria and neurophil and promoted neurite outgrowth in AD mice model.Meanwhile, VPA greatly rescued the neuronal loss in the brain of AD mice. TUNEL staining showed that VPA significantlyreduced the number of apoptotic cells. Western blot analysis revealed that VPA notably down-regulated the expressionof Caspase-3, Caspase-9 and Caspase-12, reduced the level of cytochrome C and Bax. The expression of the antiapoptoticprotein Bcl-2 was increased after VPA treatment. Flow cytometry revealed that VPA significantly decreased intracellularlevel of Ca<sup>2+</sup> and elevated mitochondrial membrane potential. Altogether, these results indicate that VPA protectedAD mice via suppression of upstream factors of apoptosis, namely inhibition of both mitochondrial and endoplasmicreticulum pathway of apoptosis.

Therapeutic Effects of Quetiapine on Memory Deficit and Brain β-Amyloid Plaque Pathology in a Transgenic Mouse Model of Alzheimer by Shenghua Zhu, Jue He, Ruiguo Zhang, Lynda Kong, Adrien Tempier, Jiming Kong, Xin-Min Li (270-278).
Our previous study has shown the preventive effects of quetiapine, an atypical antipsychotic drug, on memoryimpairment and brain pathological changes in a mouse model of Alzheimer

Benefit of 13-desmethyl Spirolide C Treatment in Triple Transgenic Mouse Model of Alzheimer Disease: Beta-Amyloid and Neuronal Markers Improvement by Eva Alonso, Paz Otero, Carmen Vale, Amparo Alfonso, Alvaro Antelo, Lydia Gimenez-Llort, Laurent Chabaud, Catherine Guillou, Luis M. Botana (279-289).
Spirolides are marine toxins that are not currently in the routine monitoring assays. Nicotinic receptors seem tobe the target of these compounds making them a promising pharmacological tool for related diseases as dementias as previouslyshown in vitro. In the present work, the bioavailability of 13-desMethyl spirolide C (13-desMeC) in the brain andin vivo effects were tested. Bioavailability was studied by ultra-performance liquid chromatography-mass spectrometryand its effect over Alzheimer hallmarks was studied by Proton magnetic resonance spectroscopy (H-MRS) and westernblot. Only 2 minutes after its intraperitoneal injection it is found in brain and remains detectable even 24 hours post administration.Based on previous works that showed beneficial effects in an in vitro model of Alzheimer

Triheptanoin Supplementation to Ketogenic Diet Curbs Cognitive Impairment in APP/PS1 Mice Used as a Model of Familial Alzheimer by Ester Aso, Jana Semakova, Laura Joda, Vladislav Semak, Lyda Halbaut, Ana Calpena, Carmen Escolano, Jose C. Perales, Isidro Ferrer (290-297).
Diets containing a high proportion of fat with respect to protein plus carbohydrates are capable of inducing ketonebody production in the liver, which provides an energetic alternative to glucose. Some ketogenic diets have beentested as therapeutic strategies for treating metabolic disorders related to a deficiency in glucose-driven ATP generation.However, ketone bodies are not capable of providing extra tricarboxylic acid cycle intermediates, limiting the anaboliccapacity of the cell. Therefore, it is reasonable to hypothesize that supplementing a ketogenic diet with anaplerotic compoundssuch as triheptanoin may improve ketogenic diet effectiveness. The present study tests this hypothesis in APP/PS1(APPswe/PS1dE9) transgenic mice, used as a model of familial Alzheimer

Hypoglycemia Induces Tau Hyperphosphorylation by Chu-Wan Lee, Yao-Hsiang Shih, Shih-Ying Wu, Tingting Yang, Chingju Lin, Yu-Min Kuo (298-308).
Cerebral hypoglycemia/hypometabolism is associated with Alzheimer

BACE1 Levels by APOE Genotype in Non-Demented and Alzheimer by Boris Decourt, Amanda Gonzales, Thomas G. Beach, Michael Malek-Ahmadi, Aaron Walker, Lucia Sue, Douglas G. Walker, Marwan N. Sabbagh (309-315).
The APOE genotype is a known susceptibility factor for Alzheimer

Pathogenesis of Abeta Oligomers in Synaptic Failure by Senthilkumar Sivanesan, Aaron Tan, Jayakumar Rajadas (316-323).
The soluble Abeta oligomers in brain are highly correlated with memory related synaptic dysfunctions in Alzheimer

Synaptic loss is the major neuropathological correlate of memory decline as a result of Alzheimer

Episodic Memory Impairment in Frontotemporal Dementia; A 99mTc- HMPAO SPECT Study by Janne M. Papma, Harro Seelaar, Inge de Koning, Djo Hasan, Ambroos Reijs, Roelf Valkema, Niels D. Prins, John C. van Swieten (332-339).

Prayer at Midlife is Associated with Reduced Risk of Cognitive Decline in Arabic Women by Rivka Inzelberg, Anne E Afgin, Magda Massarwa, Edna Schechtman, Simon D. Israeli-Korn, Rosa Strugatsky, Amin Abuful, Efrat Kravitz, Lindsay A. Farrer, Robert P. Friedland (340-346).
Midlife habits may be important for the later development of Alzheimer's disease (AD). We estimated the contributionof midlife prayer to the development of cognitive decline.

In a door-to-door survey, residents aged ≥65 years were systematically evaluated in Arabic including medical history,neurological, cognitive examination, and a midlife leisure-activities questionnaire. Praying was assessed by the number ofmonthly praying hours at midlife. Stepwise logistic regression models were used to evaluate the effect of prayer on theodds of mild cognitive impairment (MCI) and AD versus cognitively normal individuals.

Of 935 individuals that were approached, 778 [normal controls (n=448), AD (n=92) and MCI (n=238)] were evaluated. Ahigher proportion of cognitively normal individuals engaged in prayer at midlife [(87%) versus MCI (71%) or AD (69%)(p<0.0001)]. Since 94% of males engaged in prayer, the effect on cognitive decline could not be assessed in men. Amongwomen, stepwise logistic regression adjusted for age and education, showed that prayer was significantly associated withreduced risk of MCI (p=0.027, OR=0.55, 95% CI 0.33-0.94), but not AD. Among individuals endorsing prayer activity,the amount of prayer was not associated with MCI or AD in either gender.

Praying at midlife is associated with lower risk of mild cognitive impairment in women.