Volume 17, Number 3, July 2009

Pages 457-467
Review Article

Muralidhar L. Hegde, Bharathi, Anitha Suram, Chitra Venugopal, Ramya Jagannathan, Pankaj Poddar, Pullabhatla Srinivas, Kumar Sambamurti, Kosagisharaf Jagannatha Rao, Janez Scancar, Luigi Messori, Luigi Zecca, Paolo Zatta
Challenges Associated with Metal Chelation Therapy in Alzheimer’s Disease
Abstract: A close association between brain metal dishomeostasis and the onset and/or progression of Alzheimer’s disease (AD) has been clearly established in a number of studies, although the underlying biochemical mechanisms remain obscure. This observation renders chelation therapy an attractive pharmacological option for the treatment of this disease. However, a number of requirements must be fulfilled in order to adapt chelation therapy to AD so that the term “metal targeted strategies” seems now more appropriate. Indeed, brain metal redistribution rather than brain metal scavenging and removal is the major goal of this type of intervention. The most recent developments in metal targeted strategies for AD will be discussed using, as useful examples, clioquinol, curcumin, and epigallocatechin, and the future perspectives will also be outlined.

Pages 469-481
Review Article

Haim Belinson and Daniel M. Michaelson
Pathological Synergism Between Amyloid-β and Apolipoprotein E4—The Most Prevalent Yet Understudied Genetic Risk Factor for Alzheimer’s Disease
Abstract: This review focuses on apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of Alzheimer’s disease, and on in vivo and in vitro model studies of the mechanisms underlying its pathological phenotype. The review will first center on in vivo studies with transgenic mice that express human apoE4 and other human apoE alleles, and on the extent to which this model mimics and reproduces the human apoE4 phenotypes. The second part of this review will address apoE4-related in vitro studies, with particular emphasis on the effects of the state of lipidation of apoE4 on its biochemical properties and on the extent to which the in vitro results can be generalized and applied to the in vivo situation. The third part of this review will focus on a novel pharmacological in vivo system that was recently developed in our laboratory, which is based on activation of the amyloid cascade in apoE transgenic mice by prolonged inhibition of the Aβ-degrading enzyme neprilysin and on what this system and its high spatio-temporal resolution has taught us about the mechanisms underlying the pathological effects of apoE4 in vivo.

Pages 483-487
Short Communication

Amy Chan, Eugene Rogers and Thomas B. Shea
Dietary Deficiency in Folate and Vitamin E Under Conditions of Oxidative Stress Increases Phospho-Tau Levels: Potentiation by ApoE4 and Alleviation by S-Adenosylmethionine
Abstract: Prior studies link dietary deficiency and genetic risk factors for Alzheimer’s disease (AD). In the present report, mice expressing human apolipoprotein E4 (associated with increased risk of AD) and apolipoprotein E3 were subjected to a diet lacking folate and vitamin E, and containing iron as a pro-oxidant. Consistent with prior studies, E4 mice displayed more phospho-tau than E3 mice prior to dietary challenge. The deficient diet increased phospho-tau in E4 but not E3 mice, which was prevented by S-adenosyl methionine supplementation. Since neurofibrillary tangles are comprised of phospho-tau, investigation of the impact of dietary deficiency and S-adenosyl methionine supplementation on neurofibrillary tangle formation are warranted.

Pages 489-501
Rui Wang*, Suqing Wang*, James S. Malter and Deng-Shun Wang (*Equal Contributor)
Effects of 4-Hydroxy-Nonenal and Amyloid-β on Expression and Activity of Endothelin Converting Enzyme and Insulin Degrading Enzyme in SH-SY5Y Cells
Abstract: The cerebral accumulation of amyloid-β (Ab) is a consistent feature of and likely contributor to the development of Alzheimer’s disease (AD). In addition to dysregulated production, increasing experimental evidence suggests reduced catabolism plays an important role in Aβ accumulation. Although endothelin converting enzyme (ECE) and insulin degrading enzyme (IDE) degrade and thus contribute to regulating the steady-state levels of Aβ, how these enzymes are regulated remain poorly understood. In this study, we investigated the effects of 4-hydroxy-nonenal (HNE) and Aβ on the expression and activity of ECE-1 and IDE in human neuroblastoma SH-SY5Y cells. Treatment with HNE or Aβ upregulated ECE-1 mRNA and protein, while IDE was unchanged. Although both ECE-1 and IDE were oxidized within 24 h of HNE or Aβ treatment, ECE-1 catalytic activity was elevated while IDE specific activity was unchanged. The results demonstrated for the first time that both ECE-1 and IDE are substrates of HNE modification induced by Aβ. In addition, the results suggest complex mechanisms underlying the regulation of their enzymatic activity.

Pages 503-517
Ana Catarina R.G. Fonseca, Teresa Proença, Rosa Resende, Catarina R. Oliveira, Cláudia M.F. Pereira
Neuroprotective Effects of Statins in an In Vitro Model of Alzheimer’s Disease
Abstract: Statins, used as cholesterol-lowering drugs, were reported to reduce the progression of Alzheimer’s disease (AD). However, the molecular mechanisms underlying these findings remain to be clarified and it is not well understood whether this beneficial effect is due to simply lowering cholesterol levels. This study was aimed to investigate the neuroprotective effect of simvastatin and lovastatin, lipophilic statins that can transverse the blood brain barrier, against the toxicity triggered by the AD-associated amyloid-β (Aβ) peptides and to analyze if such protection is cholesterol-independent. Using primary cultures of cortical neurons treated with Aβ1-40 peptide, we have demonstrated that pre-incubation with statins prevents the rise in cytosolic Ca2+ concentration and the accumulation of reactive oxygen species induced by Aβ through mechanisms independent of cholesterol reduction. The neuroprotective actions of statins were rather attributable to their ability to reduce isoprenyl intermediates levels in the cholesterol biosynthetic pathway since their effect was reversed by geranyl pyrophosphate while cholesterol addition was ineffective. Consequently, statins were shown to rescue cortical neurons from Aβ1-40-induced caspase-3-dependent apoptosis. Moreover, our results revealed that simvastatin, at neuroprotective concentrations against Aβ-induced toxicity, is not able to activate Akt or ERK2, two signaling kinases with neuroprotective roles against apoptosis.

Pages 519-529
Suzanne M. de la Monte, Alexander Neusner, Jennifer Chu and Margot Lawton (Communicated by Paula Moreira)
Epidemilogical Trends Strongly Suggest Exposures as Etiologic Agents in the Pathogenesis of Sporadic Alzheimer’s Disease, Diabetes Mellitus, and Non-Alcoholic Steatohepatitis
Abstract: Nitrosamines mediate their mutagenic effects by causing DNA damage, oxidative stress, lipid peroxidation, and pro-inflammatory cytokine activation, which lead to increased cellular degeneration and death. However, the very same pathophysiological processes comprise the “unbuilding” blocks of aging and insulin-resistance diseases including, neurodegeneration, diabetes mellitus (DM), and non-alcoholic steatohepatitis (NASH). Previous studies demonstrated that experimental exposure to streptozotocin, a nitrosamine-related compound, causes NASH, and diabetes mellitus Types 1, 2 and 3 (Alzheimer (AD)-type neurodegeneration). Herein, we review evidence that the upwardly spiraling trends in mortality rates due to DM, AD, and Parkinson’s disease typify exposure rather than genetic-based disease models, and parallel the progressive increases in human exposure to nitrates, nitrites, and nitrosamines via processed/preserved foods. We propose that such chronic exposures have critical roles in the pathogenesis of our insulin resistance disease pandemic. Potential solutions include: 1) eliminating the use of nitrites in food; 2) reducing nitrate levels in fertilizer and water used to irrigate crops; and 3) employing safe and effective measures to detoxify food and water prior to human consumption. Future research efforts should focus on refining our ability to detect and monitor human exposures to nitrosamines and assess early evidence of nitrosamine-mediated tissue injury and insulin resistance.

Pages 531-539
Zhihou Liang, Fei Liu, Khalid Iqbal, Inge Grundke-Iqbal, Cheng-Xin Gong (Communicated by Xiongwei Zhu)
Dysregulation of Tau Phosphorylation in Mouse Brain during Excitotoxic Damage
Abstract: Glutamate receptor–mediated excitotoxicity is thought to contribute to the development of Alzheimer’s disease (AD), but the underlying mechanism is unknown. In this study, we investigated the dynamic changes of tau phosphorylation and tau-related protein kinases and protein phosphatase 2A (PP2A) in the mouse brain during excitotoxicity induced by intraperitoneal injection of 20 mg/kg kainic acid (KA). We found that KA-induced excitotoxicity led to transient dephosphorylation of tau (within 6 hr post-injection), followed by sustained hyperphosphorylation of tau at multiple sites that are hyperphosphorylated in AD brain. The initial dephosphorylation of tau may result from activation of PP2A, and the sustained hyperphosphorylation may be due mainly to activation of cdk5 and down-regulation of PP2A during the later phase. Because abnormal hyperphosphorylation of tau plays a crucial role in neurodegeneration and in the formation of neurofibrillary tangles, our results suggest that glutamate receptor–mediated excitotoxicity might contribute to AD partially via promoting abnormal hyperphosphorylation of tau in AD brain.

Pages 541-551
Sarah Jesse, Petra Steinacker, Lukas Cepek, Christine V. Arnim, Hayrettin Tumani, Stefan Lehnert, Hans A. Kretzschmar, Michael Baier, Markus Otto (Communicated by Khalid Iqbal)
Glial Fibrillary Acidic Protein and Protein S-100B: Different Concentration Pattern of Glial Proteins in Cerebrospinal Fluid of Patients with Alzheimer’s Disease and Creutzfeldt-Jakob Disease
Abstract: Glial fibrillary acidic protein (GFAP) and protein S-100B are established indicators of astrogliosis in neuropathology. As GFAP and S-100B are expressed in different cell populations, variable cerebrospinal fluid (CSF) concentrations of these proteins might reflect disease-specific pathological profiles. Therefore we investigated CSF of patients with Alzheimer's disease (AD), patients with Creutzfeldt-Jakob disease (CJD), and non-demented control patients (CON). Measurement of GFAP and S-100B in CSF was performed by commercially available ELISA. Our results show that, in AD, there are significantly higher levels of GFAP concentrations, compared to CON (p = 0.001) and CJD patients (p = 0.009), whereas S-100B is much higher in CJD, compared to AD (p = 0.001) and CON (p = 0.001). In conclusion, GFAP and S-100B represent astroglial markers and the different levels of these proteins in CSF of AD and CJD patients might point to a distinct pathophysiological involvement in these diseases. Apart from pathophysiological aspects, GFAP in particular might serve as an additional diagnostic tool for AD, due to the fact that this protein does not correlate to established markers like tau and amyloid-β such that analysis of GFAP may be useful for further differential diagnostic approaches in neurodegenerative diseases.

Pages 553-570
Laura B. Jaeger, Shinya Dohgu, Mark C. Hwang, Susan A. Farr, M. Paul Murphy, Melissa A. Fleegal-DeMotta, Jessica L. Lynch, Sandra M. Robinson, Michael L. Niehoff, Steven N. Johnson, Vijaya B. Kumar, William A. Banks
Testing the Neurovascular Hypothesis of Alzheimer’s Disease: LRP-1 Antisense Reduces Blood-brain Barrier Clearance and Increases Brain Levels of Amyloid-β Protein and Impairs Cognition
Abstract: Decreased clearance is the main reason amyloid-β protein (Aβ) is increased in the brains of patients with Alzheimer’s disease (AD). The neurovascular hypothesis states that this decreased clearance is caused by impairment of low density lipoprotein receptor related protein-1 (LRP-1), the major brain-to-blood transporter of Aβ at the blood-brain barrier (BBB). As deletion of the LRP-1 gene is a lethal mutation, we tested the neurovascular hypothesis by developing a cocktail of phosphorothioate antisenses directed against LRP-1 mRNA. We found these antisenses in comparison to random antisense selectively decreased LRP-1 expression, reduced BBB clearance of Aβ42, increased brain levels of Aβ42, and impaired learning ability and recognition memory in mice. These results support dysfunction of LRP-1 at the BBB as a mechanism by which brain levels of Aβ could increase and AD would be promoted.

Pages 571-583
Stefan J. Teipel, Thomas Meindl, Maximilian Wagner, Thomas Kohl, Katharina Bürger, Maximilian F. Reiser, Sabine Herpertz, Hans-Jürgen Möller, Harald Hampel (Communicated by Diana Woodruff-Pak)
White Matter Microstructure in Relation to Education in Aging and Alzheimer’s Disease
Abstract: The reduced risk of dementia in high-educated individuals has been suggested to reflect brain reserve capacity. In the present study, we determined the association between integrity of white matter microstructure and education separately in twenty-one patients with clinically probable Alzheimer’s disease (AD) and 18 healthy elderly subjects. We used fractional anisotropy derived from high-resolution diffusion-tensor weighted imaging at 3 Tesla as an in vivo marker of white matter microstructure. Based on multivariate network analysis, more years of education were associated with reduced white matter integrity of medial temporal lobe areas and association fiber tracts when age, gender, and dementia severity had been controlled for (p < 0.001). In controls, higher education was associated with greater white matter integrity in medial temporal lobe areas and association fiber tracts (p < 0.001). In multiple regression models, education was the main factor accounting for fiber tract integrity even when occupation was taken into account. Reduced fiber tract integrity with higher education at the same level of cognitive impairment in AD patients and higher fiber tract integrity with higher education in similar white matter areas in cognitively healthy controls agrees with the hypothesis that white matter microstructure may contribute to brain reserve capacity in humans.

Pages 585-597
Dylan W. Peterson, Roshni C. George, Francesca Scaramozzino, Nichole E. LaPointe, Richard A. Anderson, Donald J. Graves, John Lew (Communicated by James Joseph)
Cinnamon Extract Inhibits Tau Aggregation Associated with Alzheimer’s Disease In Vitro
Abstract: An aqueous extract of Ceylon cinnamon (C. zeylanicum) is found to inhibit tau aggregation and filament formation, hallmarks of Alzheimer’s disease (AD). The extract can also promote complete disassembly of recombinant tau filaments and cause substantial alteration of the morphology of paired-helical filaments isolated from AD brain. Cinnamon extract was not deleterious to the normal cellular function of tau, namely the assembly of free tubulin into microtubules. An A-linked proanthocyanidin trimer molecule was purified from the extract and shown to contain a significant proportion of the inhibitory activity. Treatment with polyvinylpyrolidone effectively depleted all proanthocyanidins from the extract solution and removed the majority, but not all, of the inhibitory activity. The remainder inhibitory activity could be attributed to cinnamaldehyde. This work shows that compounds endogenous to cinnamon may be beneficial to AD themselves or may guide the discovery of other potential therapeutics if their mechanisms of action can be discerned.

Pages 599-609
Wolff Kirsch, Grant McAuley, Barbara Holshouser, Floyd Petersen, Muhammad Ayaz, Harry V. Vinters, Cindy Dickson, E. Mark Haacke, William Britt III, James Larsen, Ivan Kim, Claudius Mueller, Matthew Schrag, Daniel Kido (Communicated by Othman Ghribi)
Serial Susceptibility Weighted MRI Measures Brain Iron and Microbleeds in Dementia
Abstract: A new iron sensitive MR sequence (susceptibility weighted imaging – SWI) enabling the simultaneous quantitation of regional brain iron levels and brain microbleeds (BMB) has been acquired serially to study dementia. Cohorts of mildly cognitively impaired (MCI) elderly (n=73) and cognitively normal participants (n=33) have been serially evaluated for up to 50 months. SWI phase values (putative iron levels) in 14 brain regions were measured and the number of BMB were counted for each SWI study. SWI phase values showed a left putaminal mean increase of iron (decrease of phase values) over the study duration in 27 participants who progressed to dementia compared to Normals (p=0.035) and stable MCI (p=0.01). BMB were detected in 9 out of 26 (38%) MCI participants who progressed to dementia and are a significant risk factor for cognitive failure in MCI participants [risk ratio = 2.06 (95% confidence interval 1.37-3.12)]. SWI is useful to measure regional iron changes and presence of BMB, both of which may be important MR-based biomarkers for neurodegenerative diseases.

Pages 611-619
Valery M. Nelson, Chanteé M. Dancik, Weiying Pan, Zhi-Gang Jiang, Michael S. Lebowitz, Hossein A. Ghanbari
PAN-811 Inhibits Oxidative Stress-Induced Cell Death of Human Alzheimer’s Disease-Derived and Age-Matched Olfactory Neuroepithelial Cells Via Suppression of Intracellular Reactive Oxygen Species
Abstract: Oxidative stress plays a significant role in neurotoxicity associated with a variety of neurodegenerative diseases including Alzheimer’s disease (AD). Increased oxidative stress has been shown to be a prominent and early feature of vulnerable neurons in AD. Olfactory neuroepithelial cells are affected at an early stage. Exposure to oxidative stress induces the accumulation of intracellular reactive oxygen species (ROS), which in turn causes cell damage in the form of protein, lipid, and DNA oxidations. Elevated ROS levels are also associated with increased deposition of amyloid-β and formation of senile plaques, a hallmark of the AD brain. If enhanced ROS exceeds the basal level of cellular protective mechanisms, oxidative damage and cell death will result. Therefore, substances that can reduce oxidative stress are sought as potential drug candidates for treatment or preventative therapy of neurodegenerative diseases such as AD. PAN-811, also known as 3-aminopyridine-2-carboxaldehyde thiosemicarbazone or Triapine, is a small lipophilic compound that is currently being investigated in several Phase II clinical trials for cancer therapy due to its inhibition of ribonucleotide reductase activity. Here we show PAN-811 to be effective in preventing or reducing ROS accumulation and the resulting oxidative damages in both AD-derived and age-matched olfactory neuroepithelial cells.

Pages 621-629
Jurgen A.H.R. Claassen, Ramon Diaz-Arrastia, Kristin Martin-Cook, Benjamin D. Levine, Rong Zhang
Altered Cerebral Hemodynamics in Early Alzheimer Disease: A Pilot Study Using Transcranial Doppler
Abstract: Cerebrovascular disease may contribute to the development and progression of Alzheimer’s disease (AD). This study investigated whether impairments in cerebral hemodynamics can be detected in early-stage AD. Nine patients with mild AD and eight cognitively normal controls matched for age underwent brain magnetic resonance imaging and neuropsychological evaluation, followed by assessment of steady-state cerebral blood flow velocity (CBFV, transcranial Doppler), blood pressure (BP, Finapres), and cerebrovascular resistance index (BP/CBFV). Cerebral hemodynamics were quantified using spectral and transfer function analysis of BP and CBFV in rest, during standing up after squat, and during repeated squat-stand maneuvers. Compared to controls, AD patients had lower CBFV and higher cerebrovascular resistance index, unexplained by brain atrophy. Low-frequency variability of BP was enhanced, suggesting impaired arterial baroreflex function. However, CBFV variability was reduced despite enhanced BP variability, and dynamic cerebral autoregulation was not impaired. In conclusion, despite a distinct pattern of altered cerebral hemodynamics, AD patients may have normal autoregulation. However, the challenges for autoregulation in AD are higher, as our data show enhanced BP fluctuations. Increased cerebral vasoconstriction or reduced vasomotion also may attenuate CBFV variability.

Pages 631-642
Qing Tian, Jun-Xia Zhang, Yao Zhang, Feng Wu, Qian Tang, Cheng Wang, Zhi-Yong Shi, Jing-Hui Zhang, Sang Liu, Yue Wang, Qi Zhang, Jian-Zhi Wang (Communicated by Xiongwei Zhu)
Biphasic Effects of Forskolin on Tau Phosphorylation and Spatial Memory in Rats
Abstract: To explore the role of protein kinase A (PKA) in regulating tau phosphorylation and spatial memory, we injected forskolin, an activator of PKA, at different concentrations into the rat brains. We found that forskolin at concentrations up to 80 μM enhanced tau phosphorylation and was associated with prominent spatial memory impairment. Higher concentrations of forskolin, up to 200 μM, were associated with reduced phosphorylation levels of tau and no memory deficits. Forskolin elevated cAMP and activated PKA in a dose-dependent manner. When infused at 200 μM, forskolin also resulted in the activation and overexpression of protein phosphatase-2A (PP-2A) and attenuated the okadaic acid-induced PP-2A inhibition. These data suggest that the upregulation of PKA by forskolin to a certain level may activate PP-2A but that the latter can ameliorate the PKA-induced tau phosphorylation and memory impairment in the rats.

Pages 643-659
Luca Ferrarini, Giovanni B. Frisoni, Michela Pievani, Johan H.C. Reiber, Rossana Ganzola, Julien Milles
Morphological Hippocampal Markers for Automated Detection of Alzheimer’s Disease and Mild Cognitive Impairment Converters in Magnetic Resonance Images
Abstract: In this study, we investigated the use of hippocampal shape-based markers for automatic detection of Alzheimer’s disease (AD) and converted mild cognitive impairment (MCI-c). Three-dimensional T1-weighted magnetic resonance images of 50 AD subjects, 50 age-matched controls, 15 MCI-c, and 15 MCI-non-converters (MCI-nc) were taken. Manual delineations of both hippocampi were obtained from normalized images. Fully automatic shape modeling was used to generate comparable meshes for both structures. Repeated permutation tests, run over a randomly sub-sampled training set (25 controls and 25 ADs), highlighted shape-based markers, mostly located in the CA1 sector, which consistently discriminated ADs and controls. Support vector machines (SVMs) were trained, using markers from either one or both hippocampi, to automatically classify control and AD subjects. Leave-1-out cross-validations over the remaining 25 ADs and 25 controls resulted in an optimal accuracy of 90% (sensitivity 92%), for markers in the left hippocampus. The same morphological markers were used to train SVMs for MCI-c versus MCI-nc classification: markers in the right hippocampus reached an accuracy (and sensitivity) of 80%. Due to the pattern recognition framework, our results statistically represent the expected performances of clinical set-ups, and compare favorably to analyses based on hippocampal volumes.

Pages 661-680
Gary W. Arendash, Takashi Mori, Chuanhai Cao, Malgorzata Mamcarz, Melissa Runfeldt, Alexander Dickson, Kavon Rezai-Zadeh, Jun Tan, Bruce A. Citron, Xiaoyang Lin, Valentina Echeverria, Huntington Potter
Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-β Levels in Aged Alzheimer’s Disease Mice
Abstract: We have recently shown that Alzheimer’s disease (AD) transgenic mice given a moderate level of caffeine intake (the human equivalent of 5 cups of coffee per day) are protected from development of otherwise certain cognitive impairment and have decreased hippocampal amyloid-β (Aβ) levels due to suppression of both β-secretase (BACE1) and presenilin 1 (PS1)/g-secretase expression. To determine if caffeine intake can have beneficial effects in “aged” APPsw mice already demonstrating cognitive impairment, we administered caffeine in the drinking water of 18-19 month old APPsw mice that were impaired in working memory. At 4-5 weeks into caffeine treatment, those impaired transgenic mice given caffeine (Tg/Caff) exhibited vastly superior working memory compared to the continuing impairment of control transgenic mice. In addition, Tg/Caff mice had substantially reduced Aβ deposition in hippocampus (down 40%) and entorhinal cortex (down 46%), as well as correlated decreases in brain soluble Aβ levels. Mechanistically, evidence is provided that caffeine suppression of BACE1 involves the cRaf-1/NFκB pathway. We also determined that caffeine concentrations within human physiological range effectively reduce active and total glycogen synthase kinase 3 levels in SweAPP N2a cells. Even with pre-existing and substantial Aβ burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD.

Pages 681-697
Chuanhai Cao, John R. Cirrito, Xiaoyang Lin, Lilly Wang, Deborah K Verges, Alexander Dickson, Malgorzata Mamcarz, Chi Zhang, Takashi Mori, Gary W. Arendash, David M. Holtzman, Huntington Potter
Caffeine Suppresses Amyloid-β Levels in Plasma and Brain of Alzheimer’s Disease Transgenic Mice
Abstract: Recent epidemiologic studies suggest that caffeine may be protective against Alzheimer’s disease (AD). Supportive of this premise, our previous studies have shown that moderate caffeine administration protects/restores cognitive function and suppresses brain amyloid-β (Aβ) production in AD transgenic mice. In the present study, we report that acute caffeine administration to both young adult and aged AD transgenic mice rapidly reduces Aβ levels in both brain interstitial fluid and plasma without affecting Aβ elimination. Long-term oral caffeine treatment to aged AD mice provided not only sustained reductions in plasma Aβ, but also decreases in both soluble and deposited Aβ in hippocampus and cortex. Irrespective of caffeine treatment, plasma Aβ levels did not correlate with brain Aβ levels or with cognitive performance in individual aged AD mice. Although higher plasma caffeine levels were strongly associated with lower plasma Aβ1-40 levels in aged AD mice, plasma caffeine levels were also not linked to cognitive performance. Plasma caffeine and theophylline levels were tightly correlated, both being associated with reduced inflammatory cytokine levels in hippocampus. Our conclusion is two-fold: first, that both plasma and brain Aβ levels are reduced by acute or chronic caffeine administration in several AD transgenic lines and ages, indicating a therapeutic value of caffeine against AD; and second, that plasma Aβ levels are not an accurate index of brain Aβ levels/deposition or cognitive performance in aged AD mice.

Pages 699-700

   Massimo Tabaton
   Coffee “Breaks” Alzheimer’s Disease

Pages 701-702
Response to Commentary

   Gary Arendash

Pages 703-717
Ava Masoumi, Ben Goldenson, Senait Ghirmai, Hripsime Avagyan, Justin Zaghi, Ken Abel, Xueying Zheng, Araceli Espinosa-Jeffrey, Michelle Mahanian, Phillip T. Liu, Martin Hewison, Matthew Mizwicki, John Cashman, Milan Fiala
1α,25-dihydroxyvitamin D3 Interacts with Curcuminoids to Stimulate Amyloid-β Clearance by Macrophages of Alzheimer’s Disease Patients
Abstract: Patients with Alzheimer’s disease (AD) suffer from brain amyloidosis related to defective clearance of amyloid-β (Aβ) by the innate immune system. To improve the innate immune system of AD patients, we studied immune stimulation of macrophages by 1α,25(OH)2-vitamin D3 (1,25D3) in combination with curcuminoids. AD patients’ macrophages segregate into Type I (positively stimulated by curcuminoids regarding MGAT-III transcription) and Type II (not stimulated). In both Type I and Type II macrophages, 1,25D3 strongly stimulated Aβ phagocytosis and clearance while protecting against apoptosis. Certain synthetic curcuminoids in combination with 1,25D3 had additive effects on phagocytosis in Type I but not Type II macrophages. In addition, we investigated the mechanisms of 1,25D3 and curcuminoids in macrophages. The 1,25D3 genomic antagonist analog MK inhibited 1,25D3 but not curcuminoid effects, suggesting that 1,25D3 acts through the genomic pathway. In silico, 1,25D3 showed preferential binding to the genomic pocket of the vitamin D receptor, whereas bisdemethoxycurcumin showed preference for the non-genomic pocket. 1,25D3 is a promising hormone for AD immunoprophylaxis because in Type I macrophages combined treatment with 1,25D3 and curcuminoids has additive effects, and in Type II macrophages 1,25D3 treatment is effective alone. Human macrophages are a new paradigm for testing immune therapies for AD.

Supplementary Data for Masoumi et al. article.

Pages 719-720
Book Review:
Metallothioneins in Biochemistry and Pathology, by Paolo Zatta, World Scientific, Hackensack, NJ, 2008, 320 pp. Reviewed by Milena Penkowa.

Pages 721-723
News Report from the Alzheimer Research Forum
Prague: What Say You, Alois—Should It Be “Alzheimer-Fischer” Disease?