Volume 25, Number 3, July 2011

Pages 385-394
Review
Aaron Barnett, Gregory J. Brewer
Autophagy in Aging and Alzheimer’s Disease: Pathologic or Protective?
Abstract: Some hypothesize that aging in humans is a cumulative process of macromolecular and mitochondrial damage starting years, even decades before any symptoms arise.  Aging may begin when the rate of damage exceeds the rate of continual repair and turnover.  Quality control for damaged mitochondria entails cellular digestion by mitophagy, a specialized kind of autophagy.  Insufficient protective autophagy could cause damaged cellular components to accumulate over many years until they affect normal function in the cell.  Alternatively, aging could be the result of overactive, pathologic autophagy.  Current knowledge supports both hypotheses with conflicting data, depending on which stage of autophagy is examined.  To distinguish these opposite hypotheses, two criteria need to be observed.  First, is there a buildup of undigested waste that can be removed by stimulation of autophagy?  Or second, if autophagy is overactive, does inhibition of autophagy rescue cell, organ and organism demise.  Both of these are best determined by rate measures rather than measures at a single time point.  Here, we review the generalized process of autophagy, with a focus on the limited information available for neuron mitophagy, aging, and Alzheimer’s disease (AD). In two mouse models, treatment with rapamycin abolishes the AD pathology and reverses memory deficits.  As a working model, we hypothesize that insufficient protective autophagy accelerates both aging and AD pathology, possibly caused by defects in autophagosome fusion with lysosomes.

Pages 395-415
Review
Greg T. Sutherland, Gerhard A. Siebert, Jillian J. Kril, George D. Mellick
Knowing Me, Knowing You: Can Knowledge of Risk Factors for Alzheimer’s Disease Prove Useful in Understanding the Pathogenesis of Parkinson’s Disease?
Abstract: Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative disorders. Why some individuals develop one disease rather than the other is not clear. Association studies with a case-control design are the time-honored approach to identifying risk factors. Extensive association studies have been carried out in both diseases creating a large knowledge database, however, reproducible risk factors remain rare. This general lack of knowledge of pathogenesis prevents us from reducing the worldwide burden of these diseases. Case-control studies are reductionist paradigms that assume, for maximum power, that the two populations being compared are exclusive and homogenous. The common occurrence of incidental AD and PD-type pathology combined with  ‘intermediate phenotypes’ such as dementia with Lewy bodies suggest that aging itself, AD, and PD are part of a complex continuum characterized by variable amounts of amyloid-β, tau, and α-synuclein pathology. This heterogeneity may be a contributor to the lack of reproducibility in association studies to date. Here, we speculate on alternative experimental approaches to the case-control paradigm and consider how the association-study literature for AD and PD might be re-interpreted in terms of a disease spectrum.

Pages 417-419
Editorial
Andrew J. Larner, Anthony G. Marson
Epileptic Seizures in Alzheimer’s Disease: Another Fine MESS?
Abstract: Much remains uncertain about epileptic seizures in the context of Alzheimer’s disease: pathogenesis, frequency, semiology, natural history, treatment.  The authors suggest a pragmatic approach to developing the evidence base in order to inform decisions on seizure treatment, based on prior pragmatic studies in epilepsy.

Pages 421-424
Short Communication
Britta Schürmann, Birgitt Wiese, Horst Bickel, Siegfried Weyerer, Steffi G. Riedel-Heller, Michael Pentzek, Cadja Bachmann, Julie Williams, Hendrik van den Bussche, Wolfgang Maier, Frank Jessen 
Association of the Alzheimer’s Disease Clusterin Risk Allele with Plasma Clusterin Concentration
Abstract: A variant within the clusterin gene has been recently associated with increased risk for Alzheimer’s disease (AD) in genome wide association studies. Here we tested the association of the respective single nucleotide polymorphisms (rs11136000) with plasma concentration of clusterin in 67 AD subjects and 191 cognitively unimpaired elderly individuals. We observed an association of the rs11136000 AD-risk variant with low clusterin plasma levels in an allele-dose dependent manner in the healthy individuals (p=0.011). This effect was numerically also present in the AD patients. We conclude that the rs11136000 AD-risk variant is associated with low clusterin plasma levels.

Pages 425-431
Maura Gallo*, Norina Marcello*, Sabrina AM Curcio, Rosanna Colao, Silvana Geracitano, Livia Bernardi, Maria Anfossi, Gianfranco Puccio, Francesca Frangipane, Alessandra Clodomiro, Maria Mirabelli, Franca Vasso, Nicoletta Smirne, Gabriella Muraca, Raffaele Di Lorenzo, Raffaele Maletta, Enrico Ghidoni, Orso Bugiani, Fabrizio Tagliavini, Giorgio Giaccone, Amalia C. Bruni *These authors contributed equally to this work
A Novel Pathogenic PSEN1 Mutation in a Family with Alzheimer’s Disease: Phenotypical and Neuropathological Features
Abstract: We report a novel presenilin1 (PSEN1) gene mutation (I143V) in a four-generation family with Alzheimer’s disease. Clinical, molecular, and neuropathological examinations were performed on index patient; thirteen affected subjects were also identified. The index patient presented at 55 with personality changes, apathy, reduction of verbal fluency, and temporal and spatial disorientation. At 68, she showed visual hallucinations; blurred language, and rigidity. She became bedridden and died at 75. A novel mutation at codon 143 was found in PSEN1 gene, changing isoleucine to valine. The brain showed severe atrophy of the frontal and temporal lobes. Parenchymal amyloid-β (Ab) deposits were abundant, diffuse to grey structures and contained Aβ42, but very few Aβ40. Amyloid angiopathy was absent. Neurofibrillary changes were severe. Our study confirms that PSEN1 mutations can be associated with unusual phenotypes. The peculiarity of the age at onset (not very early), the long course, and the frontal involvement, together with the rather complete absence of Aβ40 and of amyloid angiopathy, widen the spectrum of PSEN1-linked phenotypes.

Pages 433-444
Avdesh Avdesh, Patrick Wong, Ralph N. Martins,  Mathew T Martin-Iverson
Memory Function in a Mouse Genetic Model of Alzheimer’s Disease
Abstract: The E4 allele of the apolipoprotein E (ApoE) gene has been identified as a major risk factor for the development of late onset Alzheimer’s disease (AD). However, the mechanisms by which this gene affects AD are not fully understood. Studies of ApoE knock-out (ApoE KO) mice have revealed an exacerbation of two major pathologies that are diagnostic of AD: neurofibrillary tangles and senile plaques. However, evidence as to whether these mice have cognitive deficits is not yet conclusive. This ambiguity may arise partly from confounds associated with reliance on limited memory models, primarily, the Morris water maze task. An 8-arm radial maze task was therefore used to measure spatial memory in the ApoE KO mice, compared to controls over time. Furthermore, the effectiveness of a combination antioxidant therapy (CAT), designed to slow down the progression of AD based on concepts of oxidative stress and inflammatory processes underlying the pathology, was tested on memory ability. A significant strain difference was observed with the ApoE KO mice performing better than controls in terms of reference memory and corrects entries. No significant strain difference was observed for performance in terms of working memory errors. No significant effect of the CAT supplementation was observed.

Pages 445-453
Erin L. Abner, Richard J.  Kryscio, Frederick A. Schmitt, Karen S. SantaCruz, Gregory A. Jicha, Yushun Lin, Janna M. Neltner, Charles D. Smith, Linda J. Van Eldik, Peter T. Nelson (Handling Associate Editor: Julie Schneider)
 “End-Stage” Neurofibrillary Tangle Pathology in Preclinical Alzheimer’s Disease: Fact or Fiction?
Abstract: Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer’s disease-type pathology.  The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena.  We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals.  Data from the National Alzheimer’s Disease Coordinating Center database (n=4,690 included initially) and from the Nun Study (n=526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case.  Global cognition (final Mini-Mental State Examination scores (MMSE) and clinical ‘dementia’ status) was correlated with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology.  It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status.  There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition.

Pages 455-462
Caroline R. Elliott-Hunt, Fiona E. Holmes, Dean M. Hartley, Sylvia Perez, Elliott J. Mufson, David Wynick
Endogenous Galanin Protects Mouse Hippocampal Neurons Against Amyloid Toxicity in vitro via Activation of Galanin Receptor-2
Abstract: Expression of the neuropeptide galanin is known to be upregulated in the brain of patients with Alzheimer’s disease (AD). We and others have shown that galanin plays a neuroprotective role in a number of excitotoxic injury paradigms, mediated by activation of the second galanin receptor subtype (GAL2). In the present study, we investigated whether galanin/GAL2 plays a similar protective role against amyloid-β (Aβ)toxicity. Here we report that galanin or the GAL2/3-specific peptide agonist Gal2-11, both equally protect primary dispersed mouse wildtype (WT) neonatal hippocampal neurons from 250 nM Aβ1-42toxicity in a dose dependent manner. The amount of Aβ1-42induced cell death was significantly greater in mice with loss-of-function mutations in galanin (Gal-KO) or GAL2 (GAL2-MUT) compared to strain-matched WT controls. Conversely, cell death was significantly reduced in galanin over-expressing (Gal-OE) transgenic mice compared to strain-matched WT controls. Exogenous galanin or Gal2-11 rescued the deficits in the Gal-KO but not the GAL2-MUT cultures, confirming that the protective effects of endogenous or exogenous galanin are mediated by activation of GAL2. Despite the high levels of endogenous galanin in the Gal-OE cultures, the addition of exogenous 100 nM or 50 nM galanin or 100 nM Gal2-11 further significantly reduced cell death, implying that GAL2-mediated neuroprotection is not at maximum in the Gal-OE mice. These data further support the hypothesis that galanin over-expression in AD is a neuroprotective response and imply that the development of a drug-like GAL2 agonist might reduce the progression of symptoms in patients with AD.

Supplementary Data for Elliott-Hunt et al. article (PDF)

Pages 463-475
Jörg B. Schulz, Michael Rainer, Hans-Hermann Klünemann, Alexander Kurz, Stefanie Wolf, Kati Sternberg, Frank Tennigkeit
Sustained Effects of Once-Daily Memantine Treatment on Cognition and Functional Communication Skills in Patients with Moderate to Severe Alzheimer’s Disease: Results of a 16-Week Open-Label Trial
Abstract: The present study evaluated the effects of once-daily memantine (20 mg) treatment on cognition and communication in patients with moderate to severe Alzheimer’s disease (AD). In a multicenter, single-arm open-label study, outpatients diagnosed with AD (MMSE <20; n=97) were titrated from 5 mg to 20 mg once-daily memantine over 4 weeks. Once-daily memantine treatment (20 mg) was then continued for 8 weeks, followed by a 4-week wash-out period. The primary efficacy endpoint was the change from baseline in the Consortium to Establish a Registry for Alzheimer’s Disease -Neuropsychological Battery (CERAD-NP) total score. Secondary efficacy endpoints included change from baseline in Functional Communication Language Inventory (FLCI) and ADCS-ADL19 total score, and the response from baseline in Clinical Global Impression of Change (CGI-C). The CERAD-NP total score improved significantly after 12 weeks of once-daily memantine treatment compared with baseline (5.9 ± 8.8; p<0.0001). The FLCI total score improved significantly after 12 weeks compared with baseline (4.4 ± 6.8; p<0.0001). These significant improvements were already observed after 4 and 8 weeks of once-daily memantine treatment and persisted after a 4-week wash-out period. ADCS-ADL19 total scores showed only slight increases from baseline, and CGI-C indicated that the majority of patients experienced an improvement or stabilization of the disease after 12 weeks. At least one Treatment-Emergent Adverse Event was reported by 38 (39.2%) patients. In patients with moderate to severe AD, once-daily memantine (20 mg) treatment significantly improved cognition and functional communication and was found to have a favorable safety and tolerability profile.

Pages 477-490
Heidi I.L. Jacobs, Martin P.J. Van Boxtel, Wim van der Elst, Saartje Burgmans, Floortje Smeets, Ed H.B.M. Gronenschild, Frans R. Verhey, Harry B.M. Uylings, Jelle Jolles (Handling Associate Editor: Flavio Nobili)
Increasing the Diagnostic Accuracy of Medial Temporal Lobe Atrophy in Alzheimer’s Disease
Abstract: Medial temporal lobe (MTL) atrophy is considered to be one of the most important predictors of Alzheimer’s disease (AD). This study investigates whether atrophy in parietal and prefrontal areas increases the predictive value of MTL atrophy in three groups of different cognitive status. Seventy-five older adults were classified as cognitively stable (n = 38) or cognitively declining (n = 37) after three years follow-up. At follow-up, the grey matter of the MTL, inferior prefrontal cortex (IPC), and inferior parietal lobule (IPL) was delineated on MRI scans. Six years later, a dementia assessment resulted in distinguishing and separating a third group (n = 9) who can be considered as preclinical AD cases at scan time. Ordinal logistic regressions analysis showed that the left and right MTL, as well as the right IPC and IPL accurately predicted group membership. Receiver Operating Curves showed that the MTL was best in distinguishing cognitively stable from cognitively declining individuals. The accuracy of the differentiation between preclinical AD and cognitively stable participants improved when MTL and IPL volumes were combined, while differentiating preclinical AD and cognitively declined participants was accomplished most accurately by the combined volume of all three areas. We conclude that depending on the current cognitive status of an individual, adding IPL or IPC atrophy improved the accuracy of predicting conversion to AD by up to 22%. Diagnosis of preclinical AD may lead to more false positive outcomes if only the MTL atrophy is considered.

Pages 491-504
Christy M. Kelley, Sylvia E. Perez, Cassia Overk, David Wynick, Elliott J. Mufson (Handling Associate Editor: Diana Woodruff-Pak)
Effect of Neocortical and Hippocampal Amyloid Deposition upon Galaninergic and Cholinergic Neurites in AβPPswe/PS1ΔE9 Mice
Abstract: Amyloid-β (Aβ) plaques occur in close apposition to thickened or swollen cholinergic and galaninergic neurites within the neocortex and hippocampus in Alzheimer’s disease (AD). Despite this observation, the effect of Aβ deposition upon cholinergic and galaninergic dystrophic neurite formation remains unclear. Therefore, the purpose of this study was to evaluate the interaction between Aβ deposition within the neocortex and hippocampus upon cholinergic and galaninergic dystrophic neurite formation. Neocortical and hippocampal tissue harvested from 3- and 12-month-old amyloid-β protein precursor (AβPP)swe/PS1ΔE9 transgenic (Tg) mice were dual-immunolabeled with antibodies against either choline acetyltransferace and Aβ (10D5) or galanin (Gal) and Aβ. Stereology was used to quantify amyloid plaques and cholinergic or galaninergic dystrophic neurites. Plaque number was assessed using the optical fractionator; plaque area was calculated with the Cavalieri estimator, and dystrophic neurite numbers and thickness were manually measured. Neither amyloid nor dystrophic neuritic profiles were seen in the brains of 3-month-old Tg mice. In contrast, quantitative analysis revealed significantly more plaques in neocortex than hippocampus, with no difference in regional plaque size in 12-month-old Tg mice. Significantly more cholinergic than galaninergic dystrophic neurites-per-plaque occurred in the neocortex and hippocampus. Additionally, cholinergic dystrophic neurites were thicker than galaninergic dystrophic neurites in both regions. These data suggest that amyloid plaque deposition has a greater impact upon cholinergic than galaninergic dystrophic neurite formation in the neocortex and hippocampus in AβPP swe/PS1ΔE9 Tg mice. These data are also compatible with the hypothesis that galanin is neuroprotective and reduces dystrophic neurite formation in the face of amyloid toxicity.

Pages 505-515
Sonia Chalbot, Henrik Zetterberg, Kaj Blennow, Tormod Fladby, Niels Andreasen, Inge Grundke-Iqbal, Khalid Iqbal
Blood-Cerebrospinal Fluid Barrier Permeability in Alzheimer’s Disease
Abstract: The role of blood-cerebrospinal fluid barrier (BCB) dysfunction in Alzheimer’s disease (AD) has been addressed but not yet established. We evaluated the BCB integrity in 179 samples of cerebrospinal fluid (CSF) retrospectively collected from AD patients and control cases using both CSF/serum albumin ratio (QAlb) and CSF secretory Ca2+-dependent phospholipase A2 (sPLA2) activity. These analyses were supplemented with the measurement of total tau, amyloid-β1-42 (Aβ1-42), and ubiquitin CSF levels. We found that due to its higher sensitivity, CSF sPLA2 activity could 1) discriminate AD from healthy controls and 2) showed BCB impairment in neurological control cases while QAlb could not. Moreover, the CSF sPLA2 activity measurement showed that around half of the AD patients were characterized by a BCB impairment. The BCB dysfunction observed in AD was independent from Mini-Mental State Examination score as well as CSF levels of total tau, Aβ1-42, and ubiquitin. Finally, the BCB dysfunction was not limited to any of the CSF biomarkers-based previously identified subgroups of AD.  These results suggest that the BCB damage occurs independent of and probably precedes both Aβ and tau pathologies in a restricted subgroup of AD patients.

Pages 517-523
Jae-Hyeok Heo*, Sang-Rae Lee*, Soon-Tae Lee, Kyoung-Min Lee, Jin-Hwan Oh, Dong-Pyo Jang, Kyu-Tae Chang, Zang-Hee Cho *These authors contributed equally to this work.
Spatial Distribution of Glucose Hypometabolism Induced by Intracerebroventricular Streptozotocin in Monkeys
Abstract: Intracerebroventricular injection of streptozotocin (icv-STZ) in rodents induces cellular and behavioral features mimicking Alzheimer’s disease (AD). However, the effect of icv-STZ in terms of regional cerebral glucose metabolism has not yet been examined in vivo. Given that regionally specific hypometabolism of glucose is a consistent neuroimaging marker in early AD, we monitored 18F-deoxyglucose uptake using a high-resolution micro-PET after icv-STZ in non-human primates. Two cynomolgus monkeys (Macaca fascicularis) received STZ (2 mg/kg), and another two were given normal saline as controls, at the cerebellomedullary cistern (CM) three times (day 1, 7, and 14). FDG-PET, as well as MRI for structural evaluation, was performed immediately before, six weeks after, and 12 weeks after the first icv injection. In the STZ group, FDG uptake decreased significantly in comparison to the pre-injection baseline, at the precuneus, the posterior cingulate, and medial temporal cortices. Increase in sulcal markings suggesting brain atrophy was observed by MRI at six weeks post-injection. The structural changes normalized at 12 weeks, but the reduced FDG uptake persisted at the same loci. The cortical distribution of glucose hypometabolism was similar to that at early stages of AD patients. The findings demonstrate that the effect of icv-STZ is regionally specific, lending further support for the method as a model of AD pathogenesis.

Pages 525-533
Eva M^a Arroyo-Anllo, Stephanie Bellouard, Pierre Ingrand, Roger Gil
Effects of Automatic/Controlled Access Processes on Semantic Memory in Alzheimer’s Disease
Abstract: This study examines the impact of automatic/controlled access processes on the semantic network in 30 patients with Alzheimer’s disease (AD). The AD group was compared with a control group using a battery of neuropsychological tests, a variation of Hodges’s semantic testing battery, designed to assess semantic knowledge. The AD group had markedly lower scores than the normal group on each semantic test, but with a different degree of deterioration depending on the nature of the processes (controlled/automatic) in accessing the semantic network. AD patients had poorer performances on the explicit semantic tasks mainly involving controlled-process access (e.g., the WAIS Similarities Subtest) than those involving mainly automatic-process access (e.g., the Verbal Automatism test). Analyses of confidence intervals allowed a gradient of impaired performances in increasing order to be elaborated: a) the Verbal Automatism test, b) the WAIS Vocabulary Subtest, c) the WAIS Information Subtest, d) the Letter Fluency Task, e) Naming as a Response to Definition, f) the Category Fluency Task, g) the WAIS Similarities Subtest, and h) the Oral Denomination 80 Test. The results of our study suggest that explicit semantic tasks needing passive or automatic processes to access semantic memory would be better preserved in AD.

Pages 535-546
Gemma Manich, Clara Mercader, Jaume del Valle, Joaquim Duran-Vilaregut, Antoni Camins, Mercè Pallàs, Jordi Vilaplana, Carme Pelegrí
Characterization of Amyloid-β Granules in the Hippocampus of SAMP8 Mice
Abstract: The senescence accelerated mouse-prone 8 (SAMP8) strain of mice is an experimental model of accelerated senescence that has also been proposed as a model of Alzheimer’s disease as it shares several features with this dementia. We have recently reported amyloid-β (Aβ) granules in the hippocampus of SAMP8 mice, which contain Aβ42 and Aβ40 peptides and other amyloid-β protein precursor fragments. These granules appear clustered mainly in the stratum radiatum of the CA1 region and increase in number and size with age. Here we performed several studies to examine whether the Aβ granules in the hippocampus of SAMP8 mice contain other proteins characteristic of neuropathological aggregates, such as tau, MAP2, and α-synuclein. Moreover, we examined whether the Aβ granules in the hippocampus correspond to heparan sulphate proteoglycan (HSPG) positive granules previously described in this animal model. The results showed that Aβ granules correspond to the HSPG granular structures, being syndecan-2, a protein involved in the remodeling of dendritic spines, the type of HSPG found. Tau and MAP2, but not α-synuclein depositions, were also found in Aβ aggregates. Granules do not appear to have an astrocytic origin, since although some Aβ clusters are associated with astrocyte processes, most clusters are not. On the other hand, the presence of tau, MAP2, and NeuN in Aβ granules suggests a neuronal origin. As the components identified in Aβ granules are characteristic of the aggregates present in some neurodegenerative diseases, the SAMP8 model seems to be appropriate for the study of the processes involved in these pathologies.

Pages 547-566
Clare Peters Libeu, Karen S. Poksay, Varghese John*, Dale E. Bredesen* *Co-senior authorship
Structural and Functional Alterations in Amyloid-β Protein Precursor Induced by Amyloid-β Peptides
Abstract: Alzheimer’s disease-associated amyloid-β (Aβ) peptide is neurotoxic as an oligomer, but not as a monomer, by an unknown mechanism.  We showed previously that Aβ interacts with the amyloid-β protein precursor (AβPP), leading to caspase cleavage and cell death induction. To characterize this structure and interaction further, we purified the extracellular domain of AβPP695 (eAβPP) and its complex with Aβ oligomers (AβOs) of varying sizes, and then performed small angle X-ray scattering (SAXS).  In the absence of any Aβs, eAβPP was a compact homodimer with a tight association between the E1 and E2 domains.  Dimeric Aβ oligomers induced monomerization of eAβPP while larger oligomers also bound eAβPP but preserved the homodimer. Efficient binding of the larger oligomers correlated with the presence of prefibrillar oligomers, suggesting that the eAβPP binding is limited to a conformational subset of Aβ oligomers.  Both forms of Aβ bound to eAβPP at the Aβ-cognate region and induced dissociation of the E1 and E2 domains. Our data provide the first structural evidence for Aβ-AβPP binding and suggest a mechanism for differential modulation of AβPP processing and cell death signaling by Aβ dimers versus conformationally-specific larger oligomers.

Supplementary Data for Peters Libeu et al. article (PDF)

Page 567
Book Review: Alzheimer’s Disease and Frontotemporal Dementia: Methods and Protocols, edited by Erik D. Roberson, Humana Press, 2011, 270 p. Reviewed by Rudy J. Castellani.

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