Volume 25, Number 1, June 2011

Page 1
George Perry
Journal of Parkinson’s Disease – birth of JAD’s new sister

Pages 3-28
Review
Annakaisa Haapasalo, Dora M. Kovacs.
The many substrates of presenilin/γ-secretase
Absract: The Alzheimer's disease (AD)-associated amyloid-β protein precursor (AβPP) is cleaved by α-, b-, and presenilin (PS)/g-secretases through sequential regulated proteolysis. These proteolytic events control the generation of the pathogenic amyloid-β (Aβ) peptide, which excessively accumulates in the brains of individuals afflicted by AD. A growing number of additional proteins cleaved by PS/γ-secretase continue to be discovered. Similarly to AβPP, most of these proteins are type-I transmembrane proteins involved in vital signaling functions regulating cell fate, adhesion, migration, neurite outgrowth, or synaptogenesis. All the identified proteins share common structural features, which are typical for their proteolysis. The consequences of the PS/g-secretase-mediated cleavage on the function of many of these proteins are largely unknown. Here, we review the current literature on the proteolytic processing mediated by the versatile PS/g-secretase complex. We begin by discussing the steps of AβPP processing and PS/g-secretase complex composition and localization, which give clues to how and where the processing of other PS/γ-secretase substrates may take place. Then we summarize the typical features of PS/g-secretase-mediated protein processing. Finally, we recapitulate the current knowledge on the possible physiological function of PS/g-secretase-mediated cleavage of specific substrate proteins.

Pages 29-41
Review
Rodrigo O. Kuljiš, Melita Šalković-Petrišić (Handling Associate Editor: Gemma Casadesus)
Dementia, Diabetes, Alzheimer’s Disease, and Insulin Resistance in the Brain: Progress, Dilemmas, New Opportunities, and a Hypothesis to Tackle Intersecting Epidemics
Abstract: Dementia is an increasingly prevalent condition that intersects worldwide with the epidemic of type 2 diabetes mellitus (DM2). It would seem logical to expect that the occurrence of DM2 increases the likelihood of developing dementia, due to its deleterious effect on the cerebral vasculature and the associated hormonal and metabolic changes. Many reports indicate that it also increases the risk of developing Alzheimer’s disease (AD). However, other studies suggest that diabetes might have a relatively strong protective effect against AD, whereas genetically engineered animal models of the condition deteriorate more severely when there is a concomitant insulin resistant brain state (IRBS). Furthermore, IRBS alone is associated with anatomical, behavioral, and molecular changes that justify the proposal that AD may be due to an IRBS. This is explored in the context of accumulating evidence that the IRBS need not be related to peripheral insulin resistance, and that administration of insulin directly to the brain improves selected cognitive parameters targeted in AD. This view is consistent with the Damage Signals hypothesis of AD pathogenesis, which can help unifying the pleiotropic effects of agents toxic to insulin-producing/secreting (e.g., pancreatic β cells, as well as IRBS caused by different mechanisms in AD. Such approach may help tackling the Innovation Gap, which results from a host of factors slowing down progress towards innovative palliation and prevention of AD, as well as dementia due to complications of diabetes distinct from AD, and both conditions combined with their commonly associated metabolic and hormonal alterations.

Pages 43-46
Short Communication
Emily House, Krista Jones, Christopher Exley
Spherulites in Human Brain Tissue are Composed of Beta Sheets of Amyloid and Resemble Senile Plaques
Abstract: Recent evidence showed that amyloid-β, Aβ42, formed spherulites in vitro and, possibly, in vivo in Alzheimer’s disease brain tissue. We now confirm the presence of spherulites in human brains and that they are composed of β sheets of amyloid. The spherulites were identical in appearance to spherulites of Aβ42 formed in vitro which suggested that they may too be composed of Aβ. The physiological significance of this finding may be in its support of previous speculation that spherulites in human brain tissue are the 3-dimensional manifestations of what are otherwise identified as senile or neuritic plaques.

Pages 47-50
Short Communication
Reposo Ramírez-Lorca, Mercè Boada, Carmen Antúnez, Jesús López-Arrieta, Concha Moreno-Rey, Isabel Hernández, Juan Marín, Javier Gayán, Antonio González-Pérez, Montserrat Alegret, Lluis Tárraga, Luis M. Real,  Agustín Ruiz (Handling  Associate Editor: Benedetta Nacmias)
The MTHFD1L Gene rs11754661 Marker is Not Associated with Alzheimer's Disease in a Sample of the Spanish Population
Abstract: The MTHFD1L gene SNP variant rs11754661 was found to increase the risk of Alzheimer’s disease in a recent Whole Genome Association Study [1]. We have carried out an independent study of this genetic variant in 2467 individuals from Spain. We found no evidence of association between the MTHFD1L marker and susceptibility to Alzheimer’s disease in our sample.

Supplementary Data for Ramírez-Lorca et al. article (PDF)

Pages 51-57
Olivier Descamps, Qiang Zhang, Varghese John*, Dale E. Bredesen* (Handling Associate Editor: James Bamburg) *These two authors share senior authorship.
Induction of the C-terminal Proteolytic Cleavage of AβPP by Statins
Abstract: Statins are drugs commonly used to inhibit cholesterol synthesis, with the goal of reducing vascular diseases such as myocardial infarction and stroke.  Statins have also been suggested as a therapeutic option for Alzheimer’s disease (AD), although their benefit in AD remains controversial.  We have previously shown that the intracellular C-terminal cleavage of the amyloid-β protein precursor (AβPP) is a major contributor to the neuronal toxicity seen in AD, and that this cleavage can be induced by amyloid-β.  We now report that certain brain permeable statins are also able to induce the C-terminal cleavage of AβPP and associated cell death, whereas other statins do not.  This statin effect on AβPP exceeded the effects of all other FDA-approved drugs in a library composed of these compounds, suggesting that this effect on AβPP cleavage is unique to a subset of the statins. Furthermore, the greatest effect occurred with cerivastatin, which has previously been shown to be the statin associated with the greatest risk of rhabdomyolysis. These results may have implications for the choice of which statins to evaluate in AD therapeutic trials; furthermore, the results may inform statin choice in individuals who are at high risk for the development of AD, such as those with an apolipoprotein E ε4 allele.

Pages 59-76
Kaori Morimoto, Juri Horio, Haruhisa Satoh, Lucia Sue, Thomas Beach, Seizaburo Arita, Ikuo Tooyama, Yoshihiro Konishi (Handling Associate Editor: Yong Shen)
Expression Profiles of Cytokines in the Brains of Alzheimer’s Disease (AD) Patients Compared to the Brains of Non-Demented Patients With and Without Increasing AD Pathology
Abstract: Neuroinflammation is involved in the pathology of Alzheimer’s disease (AD). Our major focus was to clarify whether neuroinflammation plays an important role in AD pathogenesis, particularly prior to the manifestation of overt dementia. We analyzed cytokine expression profiles of the brain, with focus on non-demented patients with increasing AD pathology, referred to as high pathology control (HPC) patients, who provide an intermediate subset between AD and normal control subjects, referred to as low pathology control (LPC) patients. With real-time PCR techniques, we found significant differences in interleukin (IL)-1β, 10, 13, 18, and 33, tumor necrosis factor-α (TNFα) converting enzyme (TACE), and transforming growth factor β1 (TGFβ1) mRNA expression ratios between HPC and AD patients, while no significant differences in the expression ratios of any cytokine tested here were observed between LPC and HPC patients. The cytokine mRNA expression ratios were determined as follows: first, cytokine mRNA levels were normalized to mRNA levels of a housekeeping gene, peptidyl-prolyl isomerase A (PPIA), which showed the most stable expression among ten housekeeping genes tested here; then, the normalized data of cytokine levels in the temporal cortex were divided by those in the cerebellum, which is resistant to AD pathology. Subsequently, the expression ratios of the temporal cortex to cerebellum were compared among LPC, HPC, and AD patient groups. Our results indicate that cytokines are more mobilized and implicated in the later AD stage when a significant cognitive decline occurs and develops than in the developmental course of AD pathology prior to the manifestation of overt dementia.

Pages 77-84
Sun-Ho Han*, Eun Sun Jung*, Ji-Hoon Sohn, Hyun Joo Hong, Hyun Seok Hong, Jong Won Kim, Duk Lyul N, Manho Kim, Hee Kim, Hee Jin Ha, Young Ho Kim, Namjung Huh, Min Whan Jung, Inhee Mook-Jung *Contributed equally to this report
Human serum transthyretin levels correlate inversely with Alzheimer’s disease
Abstract: Alzheimer’s disease (AD) is the fastest growing neurodegenerative disease in the elderly population, and the search for therapeutic targets and diagnostic AD biomarkers is an exigent issue. Because amyloid-β (Aβ) aggregation constitutes the epicenter of AD pathology, Aβ-binding proteins that regulate Aβ aggregation, such as transthyretin (TTR), have attracted much attention. TTR binds to Aβ, prevents its aggregation, and consequently inhibits Aβ-induced cellular toxicity. Decreased TTR levels in cerebrospinal fluid (CSF) from AD patients suggest that TTR is a biomarker of AD. But, studies on TTR as a biomarker have focused on CSF; no study has evaluated peripheral levels of TTR in AD. Here, we examined the relationship between serum TTR levels and AD. We measured TTR levels in serum samples from 90 nondemented controls and 111 AD patients and observed significantly lower serum TTR levels in AD (p< 0.001). Notably, females in the control group had lower serum TTR levels compared with male in the control (p=0.006), while no difference in gender was noted in the AD group. There were no age-related changes in serum TTR levels. Thus, this study demonstrates a clear negative correlation between serum TTR levels and AD, suggesting that TTR is not only involved in AD pathological process but also suggested as possible peripheral biomarker for AD diagnosis in serum level.

Supplementary Data for Han et al. article (PDF)

Pages 85-91
Emmanuel Mulin, Jamie M. Zeitzer, Leah Friedman, Franck Le Duff, Jerome Yesavage, Philippe H. Robert, Renaud David
Relationship Between Apathy and Sleep Disturbance in Mild and Moderate Alzheimer’s Disease: An Actigraphic Study
Abstract: Apathy is the most frequently reported neuropsychiatric symptom across all stages of Alzheimer’s disease (AD). Both apathy and sleep disorders are known to have independent negative effects on the quality of life in individuals with AD. The aim of this study was to assess the relationship between apathy and sleep/wake patterns in individuals with AD using ambulatory actigraphy. 103 non-institutionalized individuals with AD wore a wrist actigraph continuously over seven consecutive 24-h peri­ods. Apathy was assessed using the Neuropsychiatric Inventory. Daytime mean motor activity (dMMA) was calculated from daytime wrist actigraphy data. Actigraphic parameters of sleep included total sleep time (TST), wake after sleep onset (WASO), time in bed (TIB), WASO normalized by TIB, sleep latency, and nighttime mean motor activity (nMMA). Among the 103 individuals with AD (aged 76.9 ± 7.2 years; MMSE=21.4 ± 4.3), those with apathy had significantly lower dMMA, higher WASO (both raw and normalized), and spent more time in bed during the night than those without apathy. Sleep latency, nMMA and TST did not differ significantly between the two subgroups. To our knowledge, this study is the first to identify a relationship between apathy and sleep disturbance in those with mild or moderate AD: apathy was associated with increased TIB during the night and more WASO. These results suggest that AD patients with apathy have less consolidated nocturnal sleep than those without apathy.

Pages 93-102
Linda Broer, Mohammad Arfan Ikram, Maaike Schuur, Anita L. DeStefano, Joshua C. Bis, Fan Liu, Fernando Rivadeneira, Andre G. Uitterlinden, Alexa S. Beiser, William T. Longstreth, Albert Hofman, Yurii Aulchenko, Sudha Seshadri, Annette L. Fitzpatrick, Ben A. Oostra, Monique M.B. Breteler, Cornelia M. van Duijn
Association of HSP70 and its Co-Chaperones with Alzheimer’s Disease
Abstract: The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer’s disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; n=806) and Cardiovascular Health Study (CHS; n=2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis =0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD.  These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD.

Supplementary Data for Broer et al. article (PDF)

Pages 103-109
Karen Neumann*, Gonzalo Farías*, Andrea Slachevsky, Patricio Perez, Ricardo B. Maccioni *These authors contributed equally.
Human Platelets Tau: A Potential Peripheral Marker for Alzheimer’s Disease
Abstract: Platelets are a major peripheral reservoir of the amyloid-β protein precursor, so they have been considered as a potential biological marker of Alzheimer’s disease (AD). Here, it is demonstrated that tau protein is also present in platelets and that the levels of oligomeric species of this protein could serve as a novel and reliable biological marker for AD. Blood samples were obtained from 15 AD patients and 10 paired-age controls and platelets were separated via differential centrifugation. The purity of platelets was determined by flow cytometry and microscopy and the presence of tau was determined by immunofluorescence and immunoblots with tau specific antibodies. Immunofuorescence and immunoblot patterns of platelets were positive for tau. Immunoblots also showed the presence of high molecular weight (HMW) variants of tau that appeared to correspond to oligomeric forms of the protein. The ratio of HMW tau respect to tau monomeric species was significantly higher in AD patients than controls. The present is the first description of the presence of tau in platelets. The analysis of different tau fractions in platelets could serve as a new biological marker for AD.

Pages 111-117
Hong-Lei Li*, Sheng-Sheng Shi*, Qi-Hao Guo, Wang Ni, Yi Dong, Ying Liu, Yi-Min Sun, Bei-Wang, Shen-Ji Lu, Zhen Hong, Zhi-Ying Wu *These two authors contributed equally to this work.
PICALM and CR1 Variants are not Associated with Sporadic Alzheimer’s Disease in Chinese Patients
Abstract: Alzheimer’s disease (AD) is the most common form of senile dementia, and the overall prevalence increases exponentially with age. It is well known that genetic variants may play an important role in the pathogenesis of this disorder. Recently, two independent large-scale genome-wide association studies (GWAS) identified 3 novel single nucleotide polymorphisms (SNPs) (rs11136000 within CLU, rs3851179 within PICALM and rs6656401 within CR1) that are associated with late-onset AD (LOAD), and these results have been replicated by other studies performed in the Caucasian population. Recently, an independent study failed to verify the association for the SNP within CLU in a Han Chinese population, indicating that there may be genetic heterogeneity in this association. In the present study, we studied the SNPs within PICALM and CR1 in 474 sporadic AD patients (SAD) and 591 unrelated age- and sex-matched healthy controls of Han Chinese descent. Our data revealed that the frequencies of both of these SNPs were not significantly difference between the SAD and control groups. Thus, the association between SNPs within PICALM, CR1, and SAD should be studied further in different ethnic groups.

Supplementary Data for Li et al. article (PDF)

Pages 119-133
Sarah D. Schlatterer, Matthew A. Tremblay, Christopher M. Acker, Peter Davies
Neuroinflammation in the Mouse Forebrain
Abstract: Several immunocytochemical studies have revealed that Abelson tyrosine kinase (c-Abl) is associated with both neuritic plaques and neurofibrillary tangles in the brains of patients with Alzheimer’s disease (AD). Additionally, c-Abl has been shown to phosphorylate tau on tyrosine 394. The activity of c-Abl is also involved in the control of the cell cycle and apoptosis. To examine the consequences of c-Abl activation in the adult brain, we have constructed two lines of transgenic mice expressing either a constitutively active form of c-Abl (AblPP/tTA mice) or its sister protein, Arg (ArgPP/tTA mice), with a neuron-specific promoter (CamKIIα) regulated by doxycycline (Tet-Off). Expression of active c-Abl in adult mouse forebrain neurons results in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocyctosis. Despite careful examination, no c-Abl expression is found in glial cells, indicating that neuronal c-Abl expression is responsible for the gliosis.  In contrast, ArgPP/tTA mice have no evidence of neuronal loss or gliosis, even though protein expression and kinase activity levels are similar to those in the AblPP/tTA mice. Given the evidence of c-Abl activation in the human AD brain combined with the pathological phenotype of AblPP/tTA mice, it is likely that aberrant c-Abl activity may play a role in neurodegenerative disease.

Pages 135-144
Milan Fiala, Michelle Mahanian, Mark Rosenthal, Matthew T. Mizwicki, Eric Tse, Tiffany Cho, James Sayre, Rachel Weitzman, Verna Porter
MGAT3 mRNA: A Biomarker for Prognosis and Therapy of Alzheimer’s Disease by Vitamin D and Curcuminoids
Abstract: Practical biomarkers of Alzheimer’s disease (AD) prognosis are lacking. Correspondingly, no drugs are known to decrease disease progression, although vitamin D3 has positive effects on cognition in vivo and 1α, 25-dihydroxyvitamin D3 (1,25 D3) on  amyloid-β 1-42 (Aβ) phagocytosis in vitro. We have examined in a pilot study a new biomarker in peripheral blood mononuclear cells, the transcription of mRNA of β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase (MGAT3), the essential gene for Aβ phagocytosis. The transcription of MGAT3 stimulated by Aβ distinguishes macrophagesinto Type 0 (very low MGAT3 transcription), Type I (low MGAT3 transcription up regulated by bisdemethoxycurcumin), and Type II (high MGAT3 transcription down regulated by bisdemethoxycurcumin). In this pilot study of 20 AD patients and 20 control subjects, 45% patients, but only 10% control subjects, were Type 0 (p-value= 0.009). Type 0 AD patients had worse 2-year prognosis regarding loss of independence than Type I and Type II patients (p-value=0.013). Phagocytosis of Aβ in Type I and II patients was shown to be dependent on 1,25 D3 using a specific inhibitor of the 1,25 D3-VDR activated nuclear receptor transcription factor.   In a Type II patient, recovery from cognitive dysfunction related to surgical anesthesia was preceded by an improvement in phagocytosis of Aβ. The results of this pilot study suggest that the MGAT3 Type biomarker may characterize subgroups of AD patients with different disease progression. In vitro results suggest that vitamin D3 supplementation might be beneficial in both Type I and II patients, whereas curcuminoids only in Type I. These results must be investigated in a large prospective study.

Pages 145-150
Ya-Ying Wu, Irene Han-Juo Cheng, Chin-Cheng Lee, Ming-Jang Chiu, Ming-Jen Lee, Ta-Fu Chen, Jung-Lung Hsu (Handling Associate Editor: Pei-Jung Frank Lu)
Clinical Phenotype of G206D Mutation in the Presenilin 1 Gene in Pathologically Confirmed Familial Alzheimer’s Disease
Abstract: Familial Alzheimer’s disease (FAD) is genetically heterogeneous, autosomal dominant, with nearly 100% penetrance. In FAD, most common causative genetic mutations are presenilin 1 (PSEN1), presenilin 2 and amyloid-β protein precursor. We demonstrate a family presenting as early-onset AD with a rapid deterioration course and seizure developed after 1.5 years of symptoms. A histopathological examination of the frontal cortex showed amyloid deposition and abundant phosphorylated tau deposition. In both cases, a single nucleotide mutation from guanine to adenine at exon 7 was found in PSEN1 (c.617G>A, codon change from GGT to GAT). Though G206D mutation in PSEN1 gene was found in FAD, no clinical phenotype or pathological finding was documented. This is the first report of PSEN1 mutation (Gly206Asp) with features of seizure and a rapid progressive cognitive decline in a pathologically confirmed case of FAD.

Supplementary Data for Schlatterer et al. article (COMING SOON)

Pages 151-162
Loukia Katsouri*, Callum Parr*, Nenad Bogdanovic, Michael Willem, Magdalena Sastre (Handling Associate Editor: Elena Galea) *These authors contributed equally to this work.
PPARγ Co-Activator-1α (PGC-1α) Reduces Amyloid-β Generation Through a PPARγ-Dependent Mechanism
Abstract: We have previously reported that the nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) regulates the transcription of β-secretase (BACE1), a key enzyme involved in amyloid-β (Aβ) generation. Here, we aimed to investigate the role of PPARγ coactivator-1α (PGC-1α), which controls major metabolic functions through the co-activation of PPARγ and other transcription factors. Western blotting experiments with nuclear extracts from brain cortex of AD cases and controls showed a reduction in the levels of PGC-1α in AD patients. PGC-1α overexpression in N2a neuroblastoma cells induced a decrease in the levels of secreted Aβ and an increase in the levels of non-amyloidogenic soluble AβPPα.  The decrease in Aβ after exogenous expression of PGC-1α was a consequence of reduced BACE1 expression and transcription, together with a decrease in BACE1 promoter activity. In addition, we detected a significant reduction in β-secretase activity by measuring the levels of β-carboxy terminus fragment (β-CTFs) and by using a commercial assay for β-secretase. In contrast, down-regulation of PGC-1α levels by transfection with PGC-1α siRNA increased BACE1 expression. These effects appeared to be dependent on PPARγ, because PGC-1α did not affect Aβ and BACE1 levels in N2a cells transfected with PPARγ siRNA or in PPARγ knockout fibroblasts. In conclusion, since PGC-1α appears to decrease Aβ generation, therapeutic modulation of PGC-1α could have real potential as a treatment for AD.

Supplementary Data for Katsouri et al. article (COMING SOON)

Pages 163-173
Emily H. Trittschuh, Paul K. Crane, Eric B. Larson, Brenna Cholerton, Wayne C. McCormick, Susan M. McCurry, James D. Bowen, Laura D. Baker, Suzanne Craft
Effects of Varying Diagnostic Criteria on Prevalence of Mild Cognitive Impairment in a Community Based Sample
Abstract: Mild cognitive impairment (MCI) is proposed to be a prodrome to dementia in some older adults. However, the presentation of MCI in the community can differ substantially from clinic-based samples. The aim of the current study is to demonstrate the effects of different operational definitions of MCI on prevalence estimates in community-dwelling older adults. A consecutive series of 200 participants aged 65 and over from the Adult Changes in Thought (ACT) community-based cohort were approached to undergo comprehensive neuropsychological and medical evaluation; 159 were included in the final analyses.  Nondemented subjects were categorized using various diagnostic criteria for MCI.  In a novel approach, neuropsychological test scores were evaluated using an individualized benchmark as a point of test comparison, as well as traditional methods that entail comparison to age-based normative data.  Diagnostic criteria were further subdivided by severity of impairment (1.0 vs. 1.5 standard deviations [sd] below the benchmark) and extent of impairment (based on a single test or an average of tests within a cognitive domain).  MCI prevalence rates in the sample were highly dependent on these diagnostic factors, and varied from 11% to 92% of the sample.  Older groups tended to show higher prevalence rates, although this was not the case across all diagnostic schemes.  The use of an individualized benchmark, less severe impairment cutoff, and impairment on only a single test all produced higher rates of MCI. Longitudinal follow-up will determine whether varying diagnostic criteria improves sensitivity and specificity of the MCI diagnosis as a predictor for dementia.

Pages 175-176
Book Review: Aging and Age-Related Disorders edited by S. Bondy and K Maiese. New York, Springer, 2010, ISBN 978-1-60761-602-3. Reviewed by George M. Martin

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