1.
Cerebrospinal Fluid Levels of β-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia.
Source
Neuropsychiatric Clinic, Skåne University Hospital, S-20502 Malmö, Sweden. oskar.hansson@med.lu.se.
Abstract
CONTEXT:
Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease.
OBJECTIVES:
To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau(P-tau), and β-amyloid 1-42 (Aβ42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD.
DESIGN:
A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years).
SETTING:
Memory disorder clinic. Patients A total of 137 patients with MCI who underwent lumbar puncture at baseline. Main Outcome Measure Conversion to AD dementia.
RESULTS:
During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Aβ42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P < .001). Baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Aβ42:P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%.
CONCLUSIONS:
Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Aβ42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration.
The role of mTOR signaling in Alzheimer disease.
Source
Department of Physiology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio. 7703 Floyd Curl Drive, San Antonio, TX 78229.
Abstract
The buildup of Abeta and tau is believed to directly cause or contribute to the progressive cognitive deficits characteristic of Alzheimer disease. However, the molecular pathways linking Abeta and tau accumulation to learning and memory deficits remain elusive. There is growing evidence that soluble forms of Abeta and tau can obstruct learning and memory by interfering with several signaling cascades. In this review, I will present data showing that the mammalian target of rapamycin (mTOR) may play a role in Abeta and tau induced neurodegeneration.
- PMID:
- 22202101
- [PubMed - in process]
Does Alzheimer's disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (I).
Source
Instituto Cajal, CSIC, Madrid, España.
Abstract
INTRODUCTION:
Many publications consider that the Alzheimer's disease (AD) is exclusive to the human species, and that no other animal species suffers from the disease. However, various studies have shown that some species can present with some of the defining characteristics of the disease in humans, both in the neuropathological changes and cognitive-behavioural symptoms.
DEVELOPMENT:
In this work, the results published (PubMed) on the senile brain changes in non-human primates of different degrees of evolution, are reviewed. The neuropathological changes associated with the accumulation of amyloid or highly phosphorylated tau protein are rare outside the primate order, but in all the sub-orders, families, genera and species of non-human primates that have been studied, some senile individuals have shown amyloid accumulation in the brain. Even in some species the presence of these deposits in senility is constant. Changes related to the accumulation of tau protein, are always of very little significance, and have been detected only in some non-human primate species, both little evolved and highly evolved. In different species of non-human primates, some types of cognitive-behavioural changes are present in some senile individuals with greater intensity when compared with both normal adult individuals and other senile individuals of the species. The importance of the determination of the longevity of the species in different habitats (natural habitats, new habitats, semi-liberty, captivity) is stressed in these studies.
CONCLUSIONS:
Morphological and histochemical and cognitive-behavioural features similar to those observed in normal aged man are present in senile non-human primates. Moreover, other characteristics of the non-human primates could be indicative of a pathological «Alzheimer type» ageing.
Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.
Amyloid pathology in persons with "normal" cognition.
Source
From the Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.
Abstract
Alzheimer disease (AD) is characterized pathologically by cortical neuritic plaques composed of a central core of amyloid-β (Aβ) peptide fibrils and neurofibrillary tangles composed of abnormally phosphorylated tau. The deposition of Aβ is thought to be an early step in a cascade of events that ultimately leads to the loss of cognitive abilities and dementia that characterizes AD. Thus, it was not surprising to find AD pathology in persons with mild cognitive impairment (MCI).(1) Clinical-pathologic studies have also reported a relation between AD pathology and cognition in persons without MCI or dementia.(2) Over the past several years, clinical-pathologic studies have been confirmed with in vivo imaging of amyloid by PET using Pittsburgh compound B (PiB).(3) Overall, these findings have led to a new conceptualization of AD as beginning with an asymptomatic pathophysiologic process, followed by a MCI stage, and ultimately the final AD dementia stage.(4,5) Understanding factors that influence the onset and progression of AD is of great interest. The apolipoprotein E ε4 allele polymorphism (APOE) is the most important genetic risk factor for AD and may increase disease risk, in part, by influencing Aβ clearance and fibrillogenesis.(6) In fact, some clinical-pathologic data suggest that Aβ mediates the association of APOE with cognition, at least in studies that include the full range of cognition.(7) However, the influence of APOE on Aβ and cognition among persons without cognitive impairment has not been well studied. In this issue of Neurology®, Kantarci et al.(8) use data from the Mayo Clinic Study of Aging (MCSA) to examine the relation of APOE to Aβ identified by PiB PET imaging and cognitive function in persons without cognitive impairment.
Interaction between pathogenic proteins in neurodegenerative disorders.
Source
Institute of Clinical Neurobiology, Vienna, Austria.
Abstract
The misfolding and progressive aggregation of specific proteins in selective regions of the nervous system is a seminal occurrence in many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, increasing evidence indicates considerable overlap between synucleinopathies, tauopathies and other protein-misfolding diseases. Inclusions, often characteristic hallmarks of these disorders, suggest interactions of pathological proteins enganging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Alzheimer, Parkinson, Huntington, and prion diseases, have confirmed correlations/overlaps between these and other neurodegenerative disorders. Emerging evidence, in addition to synergistic effects of tau protein, amyloid β, α-synuclein, and other pathologic proteins, suggests that prion-like induction and spreading, involving secreted proteins, are major pathogenic mechanisms in various neurodegenerative diseases, depending on genetic backgrounds and environmental factors. The elucidation of the basic molecular mechanisms underlying the interaction and spreading of pathogenic proteins, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, is a major challenge for modern neuroscience, in order to provide a deeper insight into their pathogenesis as a basis of effective diagnosis and treatment. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
Mechanistic involvement of the calpain-calpastatin system in Alzheimerneuropathology.
Source
*Laboratory for Proteolytic Neuroscience, Rikagaku Kenkyūjo (RIKEN) Brain Science Institute, Wako, Saitama, Japan;
Abstract
The mechanism by which amyloid-β peptide (Aβ) accumulation causes neurodegeneration in Alzheimer's disease (AD) remains unresolved. Given that Aβ perturbs calcium homeostasis in neurons, we investigated the possible involvement of calpain, a calcium-activated neutral protease. We first demonstrated close postsynaptic association of calpain activation with Aβ plaque formation in brains from both patients with AD and transgenic (Tg) mice overexpressing amyloid precursor protein (APP). Using a viral vector-based tracer, we then showed that axonal termini were dynamically misdirected to calpain activation-positive Aβ plaques. Consistently, cerebrospinal fluid from patients with AD contained a higher level of calpain-cleaved spectrin than that of controls. Genetic deficiency of calpastatin (CS), a calpain-specific inhibitor protein, augmented Aβ amyloidosis, tau phosphorylation, microgliosis, and somatodendritic dystrophy, and increased mortality in APP-Tg mice. In contrast, brain-specific CS overexpression had the opposite effect. These findings implicate that calpain activation plays a pivotal role in the Aβ-triggered pathological cascade, highlighting a target for pharmacological intervention in the treatment of AD.-Higuchi, M., Iwata, N., Matsuba, Y., Takano, J., Suemoto, T., Maeda, J., Ji, B., Ono, M., Staufenbiel, M., Suhara, T., Saido, T. C. Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology.
Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort.
Source
Correspondence and reprint requests to Dr. Schoonenboom: niki.schoonenboom@vumc.nl.
Abstract
OBJECTIVE:
To determine how amyloid β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels in CSF behave in a large cohort of patients with different types of dementia.
METHODS:
Baseline CSF was collected from 512 patients with Alzheimer disease (AD) and 272 patients with other types of dementia (OD), 135 patients with a psychiatric disorder (PSY), and 275 patients with subjective memory complaints (SMC). Aβ42, t-tau, and p-tau (at amino acid 181) were measured in CSF by ELISA. Autopsy was obtained in a subgroup of 17 patients.
RESULTS:
A correct classification of patients with AD (92%) and patients with OD (66%) was accomplished when CSF Aβ42 and p-tau were combined. Patients with progressive supranuclear palsy had normal CSF biomarker values in 90%. Patients with Creutzfeldt-Jakob disease demonstrated an extremely high CSF t-tau at a relatively normal CSF p-tau. CSF AD biomarker profile was seen in 47% of patients with dementia with Lewy bodies (DLB), 38% in corticobasal degeneration (CBD), and almost 30% in frontotemporal lobar degeneration (FTLD) and vascular dementia (VaD). PSY and SMC patients had normal CSF biomarkers in 91% and 88%. Older patients are more likely to have a CSF AD profile. Concordance between clinical and neuropathologic diagnosis was 85%. CSF markers reflected neuropathology in 94%.
CONCLUSION:
CSF Aβ42, t-tau, and p-tau are useful in differential dementia diagnosis. However, in DLB, FTLD, VaD, and CBD, a substantial group exhibit a CSF AD biomarker profile, which requires more autopsy confirmation in the future.
Localized hippocampus measures are associated with Alzheimer pathology and cognition independent of total hippocampal volume.
Source
Department of Neurology, School of Medicine, University of California, Davis, Davis, CA, USA; Graduate Group in Computer Science, School of Engineering, University of California, Davis, Davis, CA, USA.
Abstract
Hippocampal injury in the Alzheimer's disease (AD) pathological process is region-specific and magnetic resonance imaging (MRI)-based measures of localized hippocampus (HP) atrophy are known to detect region-specific changes associated with clinical AD, but it is unclear whether these measures provide information that is independent of that already provided by measures of total HP volume. Therefore, this study assessed the strength of association between localized HP atrophy measures and AD-related measures including cerebrospinal fluid (CSF) amyloid beta and tauconcentrations, and cognitive performance, in statistical models that also included total HP volume as a covariate. A computational technique termed localized components analysis (LoCA) was used to identify 7 independent patterns of HP atrophy among 390 semiautomatically delineated HP from baseline magnetic resonance imaging of participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Among cognitively normal participants, multiple measures of localized HP atrophy were significantly associated with CSF amyloid concentration, while total HP volume was not. In addition, among all participants, localized HP atrophy measures and total HP volume were both independently and additively associated with CSF tau concentration, performance on numerous neuropsychological tests, and discrimination between normal, mild cognitive impairment (MCI), and AD clinical diagnostic groups. Together, these results suggest that regional measures of hippocampal atrophy provided by localized components analysis may be more sensitive than total HP volume to the effects of AD pathology burden among cognitively normal individuals and may provide information about HP regions whose deficits may have especially profound cognitive consequences throughout the AD clinical course.
Copyright © 2011 Elsevier Inc. All rights reserved.
BETA-AMYLOID CARRYING THE DUTCH MUTATION HAS DIVERSE EFFECTS ON CALPAIN-MEDIATED TOXICITY IN HIPPOCAMPAL NEURONS.
Source
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Abstract
Hereditary cerebral hemorrhage with amyloidosis-Dutch type is a disorder associated with a missense mutation (E693Q) in the beta-amyloid (Aβ)-coding region of the amyloid precursor protein. This familial disease is characterized by cognitive deficits secondary to intracerebral hemorrhage and, in some cases, progressive Alzheimer disease (AD)-like dementia. Although this mutation was the first ever reported in the human APP gene, little is known about the molecular mechanisms underlying the direct toxic effects of this mutated Aβ on central neurons. In the present study, we assessed the role of calpain-mediated toxicity in such effects using an AD primary culture model system. Our results showed that Dutch mutant Aβ (E22Q) induced calpain-mediated cleavage of dynamin 1 and a significant decrease in synaptic contacts in mature hippocampal cultures. These synaptic deficits were similar to those induced by wild type Aβ. In contrast, calpain-mediated tau cleavage leading to the generation of a 17 kDa neurotoxic fragment, as well as neuronal death, were significantly reduced in E22Q Aβ-treated neurons when compared to WT Aβ-treated ones. This complex regulation of the calpain-mediated toxicity pathway by E22Q Aβ could have some bearings in the pathobiology of this familial AD form.
Cerebrospinal Fluid Proteins Predict Longitudinal Hippocampal Degeneration in Early-stage Dementia of the Alzheimer Type.
Source
*Northwestern University Feinberg School of Medicine, Chicago, IL †Washington University School of Medicine, St. Louis, MO ‡Simon Frasier University, Vancouver, BC, Canada.
Abstract
OBJECTIVE:
Biomarkers are needed to improve the sensitivity and accuracy of diagnosis, and also prognosis, in individuals with early Alzheimer disease (AD). Measures of brain structure and disease-related proteins in the cerebrospinal fluid (CSF) have been proposed as biomarkers, yet relatively little is known about the relationships between such measures. The present study was conducted to assess the relationship between CSF Aβ and tau protein levels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of theAlzheimer type.
DESIGN:
A single CSF sample and longitudinal magnetic resonance scans were collected. The CSF samples were assayed for tau, phosphorylated tau181 (p-tau181), Aβ1-42, and Aβ1-40 using an enzyme-linked immunosorbent assay. Large-deformation diffeomorphic metric mapping was used to generate hippocampal surfaces, and a composite hippocampal surface (previously constructed from 86 healthy participants) was used as a structural reference.
PATIENTS OR OTHER PARTICIPANTS:
Thirteen participants with very mild AD (Clinical Dementia Rating, CDR 0.5) and 11 cognitively normal participants (CDR 0).
INTERVENTION:
None.
MAIN OUTCOME MEASURES:
Initial and rate-of-change measures of total hippocampal volume and displacement of the hippocampal surface within zones overlying the CA1, subiculum, and CA2-4+DG cellular subfields, and their correlations with initial CSF measures.
RESULTS:
Lower CSF Αβ1-42 levels and higher tau/Αβ1-42 and p-tau181/Αβ1-42 ratios were strongly correlated with decreases in hippocampal volume and measures of progressive inward deformations of the CA1 subfield in participants with early AD, but not in cognitively normal participants.
CONCLUSIONS:
Despite the small sample size, we found that Αβ1-42 related and tau-related CSF measures were associated with hippocampal degeneration in individuals with clinically diagnosed early AD and may reflect an association with a common underlying disease mechanism.
[Role of biomarkers in the early diagnosis of Alzheimer's disease].
Source
Unidad de Alzheimer y Otros Trastornos Cognitivos, Servicio de Neurología, ICN, Hospital Clínic de Barcelona, Barcelona, España.
Abstract
Alheimer's disease is the most frequent cause of cognitive decline and behavioral abnormalities in adults. Diagnosis is currently made in the advanced phases. An an early diagnosis in the prodromal phase (or earlier if possible) is required for the prevention of this disease, its early management and the development of potential therapies that could alter its natural course. The syndromic concept of mild cognitive impairment (the presence of detectable and quantifiable deterioration in one of the cognitive domains but without affecting -or without substantially affecting- autonomic performance of instrumental function) and its variants has aided understanding of the predementia stages of Alheimer'sdisease, even though its etiology may involve multiple factors. The use of biomarkers such as determination of the proteins involved in the disease in cerebrospinal fluid (Aβ42-amyloid, total and phosphorylated tau) and measurement of the hippocampus and entorhinal cortex with magnetic resonance imaging and positron emission tomography (both glucose and amyloid measurements), alone or combined, could allow early and etiologic diagnosis. Patients withAlzheimer's disease show reduced Aβ42-amyloid levels and increased total and phosphorylated tau levels in cerebrospinal fluid.
Copyright © 2011 SEGG. Published by Elsevier Espana. All rights reserved.
Evidence for Elevated Cerebrospinal Fluid ERK1/2 Levels in AlzheimerDementia.
Source
Department of Psychiatry and Psychotherapy, Laboratory for Molecular Neurobiology, LVR-Klinikum Essen, University of Duisburg-Essen, Virchowstraße 174, 45147 Essen, Germany.
Abstract
Cerebrospinal fluid (CSF) samples from 33 patients with Alzheimer dementia (AD), 21 patients with mild cognitive impairment who converted to AD during followup (MCI-AD), 25 patients with stable mild cognitive impairment (MCI-stable), and 16 nondemented subjects (ND) were analyzed with a chemiluminescence immunoassay to assess the levels of the mitogen-activated protein kinase ERK1/2 (extracellular signal-regulated kinase 1/2). The results were evaluated in relation to total Tau (tTau), phosphorylated Tau (pTau), and beta-amyloid 42 peptide (Aβ42). CSF-ERK1/2 was significantly increased in the AD group as compared to stable MCI patients and the ND group. Western blot analysis of a pooled cerebrospinal fluid sample revealed that both isoforms, ERK1 and ERK2, and low amounts of doubly phosphorylated ERK2 were detectable. As a predictive diagnostic AD biomarker, CSF-ERK1/2 was inferior to tTau, pTau, and Aβ42.
Molecular imaging in Alzheimer's disease: new perspectives on biomarkers for early diagnosis and drug development.
Source
Karolinska Institutet, Alzheimer Neurobiology Center, Karolinska University, Hospital Huddinge, Novum 5th floor, 141 86 Stockholm, Sweden. alexander.kroll@biomedcentral.com.
Abstract
ABSTRACT: Recent progress in molecular imaging has provided new important knowledge for further understanding the time course of early pathological disease processes in Alzheimer's disease (AD). Positron emission tomography (PET) amyloid beta (Aβ) tracers such as Pittsburgh Compound B detect increasing deposition of fibrillar Aβ in the brain at the prodromal stages of AD, while the levels of fibrillar Aβ appear more stable at high levels in clinical AD. There is a need for PET ligands to visualize smaller forms of Aβ, oligomeric forms, in the brain and to understand how they interact with synaptic activity and neurodegeneration. The inflammatory markers presently under development might provide further insight into the disease mechanism as well as imaging tracers for tau. Biomarkers measuring functional changes in the brain such as regional cerebral glucose metabolism and neurotransmitter activity seem to strongly correlate with clinical symptoms of cognitive decline. Molecular imaging biomarkers will have a clinical implication in AD not only for early detection of AD but for selecting patients for certain drug therapies and to test disease-modifying drugs. PET fibrillar Aβ imaging together with cerebrospinal fluid biomarkers are promising as biomarkers for early recognition of subjects at risk for AD, for identifying patients for certain therapy and for quantifying anti-amyloid effects. Functional biomarkers such as regional cerebral glucose metabolism together with measurement of the brain volumes provide valuable information aboutdisease progression and outcome of drug treatment.
Interaction between α-synuclein and other proteins in neurodegenerative disorders.
Source
Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria. kurt.jellinger@univie.ac.at
Abstract
Protein aggregation is a common characteristic of many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, evidence increasingly indicates considerable overlap between synucleinopathies and tauopathies or other protein-misfolding diseases. Inclusions, characteristics of these disorders, also occurring in other neurodegenerative diseases, suggest interactions of pathological proteins engaging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Parkinson and Alzheimer diseases have confirmed correlations/overlaps between these and other neurodegenerative disorders. The synergistic effects of α-synuclein, hyperphosphorylated tau, amyloid-β, and other pathologic proteins, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, are critically reviewed, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, although the etiology of most of these processes is still mysterious.
Long-term oral intake of aluminium or zinc does not accelerate Alzheimerpathology in AβPP and AβPP/tau transgenic mice.
Source
Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science Department of Human Life Science, Showa Women's University Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Juntendo University, Tokyo Department of Pharmacology, International University of Health and Welfare, Tochigi, Japan.
Abstract
Whether or not the oral intake of metals such as aluminium (Al) and zinc (Zn) is a risk for Alzheimer's disease (AD) has been a matter of controversy. Lack of AD pathology in patients with Al encephalopathy indicates Al does not cause AD. On the other hand, some epidemiological studies have suggested high Al increases the occurrence of AD. Our purpose is to test if high Al in drinking water is a risk factor for AD. We administered Al and Zn in drinking water to Tg2576, a transgenic mouse model for amyloid β-protein (Aβ) deposition with the Aβ precursor protein (AβPP) mutations (K670N/M671L), and Tg2576/tau(P301L), a model for Aβ and tau deposition. Deionized water was given to the control Tg2576 and Tg2576/tau. After administration for 4-10 months of approximately 100 mg/kg body weight Al or Zn per day, we were not able to find by quantitative immunohistochemical analyses differences in the deposition of Aβ and taubetween the treated and untreated groups. Nor did the Al or Zn treatment affect the amount of soluble Aβ and Aβ*56, an Aβ oligomer, measured by ELISA or immunoblot. The oral intake of excess Al or Zn does not accelerate AD pathology in the transgenic mouse models for Aβ and tau accumulation. Such results do not seem to support the notion that excessive oral intake of Al or Zn is a risk factor for AD.
© 2011 Japanese Society of Neuropathology.
Insights into Mitochondrial Dysfunction: Aging, Amyloid-β and Tau - a deleterious trio.
Source
Universitäre Psychiatrische Kliniken Basel, Neurobiology Lab for Brain Aging & Mental Health, Basel, Switzerland; karen.schmitt@upkbs.ch.
Abstract
Significance. Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder mainly affecting elderly individuals. The pathology of AD is characterized by amyloid plaques (aggregates of amyloid-β (Aβ)) and neurofibrillary tangles (aggregates of tau), but the mechanisms underlying this dysfunction are still partially unclear. Recent Advances. A growing body of evidence supports mitochondrial dysfunction as a prominent and early, chronic oxidative stress-associated event that contributes to synaptic abnormalities and, ultimately, selective neuronal degeneration in AD. Critical issues. In this review, we discuss on the one hand whether mitochondrial decline observed in brain aging is a determinant event in the onset of AD and on the other hand the close inter-relationship of this organelle with Aβ and tauin the pathogenic process underlying AD. Moreover, we summarize evidence from aging and Alzheimer models showing that the harmful trio "aging, Aβ and tau protein" triggers mitochondrial dysfunction through a number of pathways, such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production and interaction with mitochondrial proteins, contributing to the development and progression of the disease. Future Directions. The aging process may weaken the mitochondrial OXPHOS system in a more general way over many years providing a basis for the specific and destructive effects of Aβ and tau. Establishing strategies involving efforts to protect cells at the mitochondrial level by stabilizing or restoring mitochondrial function and energy homeostasis appears to be challenging, but very promising route on the horizon.
(Val(8)) glucagon-like peptide-1 prevents tau hyperphosphorylation, impairment of spatial learning and ultra-structural cellular damage induced by streptozotocin in rat brains.
Source
Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, PR China.
Abstract
It has being shown that glucagon-like peptide-1 (GLP-1), a new anti-diabetes agent, significantly attenuated beta-amyloid (Aβ) levels in rats. In the present study, (Val(8))GLP-1 was used to prevent impairments in memory formation,tau hyperphosphorylation and ultra-structural changes induced by streptozotocin intracerebroventricular (i.c.v.) injection. A spatial water maze task was used to test the rats' learning and memory formation, Western blot was used to measuretau hyperphosphorylation/total tau, and transmission electron microscope was used to find ultra-structural changes. The results shown that streptozotocin induced a series of Alzheimer disease -like changes in behaviour, a significant decline in learning and memory formation, an increased expression of total tau and an increased ratio of phosphorylated tau, and damage to nucleus and nucleolus as seen in electron micrographs. After treatment with (Val(8))GLP-1 (50μM in 10μl i.c.v.), there is a significant improvement in learning and memory, a reduction in total tau expression and hyperphosphorylated tau levels, and a recovery of damaged cell nuclei and nucleolus. Our results indicated that (Val(8))GLP-1 might prevent age-related neurodegenerative changes by preventing decline of learning and memory formation, reduction of phosphorylated tau levels and protection of subcellular structures and morphology of neurons. Therefore, (Val(8))GLP-1 is potentially a novel treatment for Alzheimer's disease.
Copyright © 2011. Published by Elsevier B.V.
Alzheimer disease biomarkers are associated with body mass index.
Source
Department of Neurology, University of Kansas School of Medicine, Kansas City, KS 66160, USA.
Abstract
OBJECTIVE:
Both low and high body mass index (BMI) has been associated with cognitive impairment and dementia risk, including Alzheimer disease (AD). We examined the relationship of BMI with potential underlying biological substrates for cognitive impairment.
METHODS:
We analyzed cross-sectional data from participants enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with PET imaging using Pittsburgh Compound B (PiB, n = 101) or CSF analyses (n = 405) for β-amyloid peptide (Aβ) and total tau. We assessed the relationship of CSF biomarkers and global PiB uptake with BMI using linear regression controlling for age and sex. We also assessed BMI differences between those who were and were not considered biomarker positive. Finally, we assessed BMI change over 2 years in relationship to AD biomarkers.
RESULTS:
No dementia, mild cognitive impairment (MCI), and AD groups were not different in age, education, or BMI. In the overall sample, CSF Aβ (β = 0.181, p < 0.001), tau (β = -0.179, p < 0.001), tau/Aβ ratio (β = -0.180, p < 0.001), and global PiB uptake (β = -0.272, p = 0.005) were associated with BMI, with markers of increased AD burden associated with lower BMI. Fewer overweight individuals had biomarker levels indicative of pathophysiology (p < 0.01). These relationships were strongest in the MCI and no dementia groups.
CONCLUSIONS:
The presence and burden of in vivo biomarkers of cerebral amyloid and tau are associated with lower BMI in cognitively normal and MCI individuals. This supports previous findings of systemic change in the earliest phases of the disease. Further, MCI in those who are overweight may be more likely to result from heterogeneous pathophysiology.
Defects in the medial entorhinal cortex and dentate gyrus in the mouse model of Sanfilippo syndrome type B.
Source
Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Abstract
Sanfilippo syndrome type B (MPS IIIB) is characterized by profound mental retardation in childhood, dementia and death in late adolescence; it is caused by deficiency of α-N-acetylglucosaminidase and resulting lysosomal storage of heparan sulfate. A mouse model, generated by homologous recombination of the Naglu gene, was used to study pathological changes in the brain. We found earlier that neurons in the medial entorhinal cortex (MEC) and the dentate gyrus showed a number of secondary defects, including the presence of hyperphosphorylated tau (Ptau) detected with antibodies raised against Ptau in Alzheimer disease brain. By further use of immunohistochemistry, we now show staining in neurons of the same area for beta amyloid, extending the resemblance to Alzheimer disease. Ptau inclusions in the dentate gyrus of MPS IIIB mice were reduced in number when the mice were administered LiCl, a specific inhibitor of Gsk3β. Additional proteins found elevated in MEC include proteins involved in autophagy and the heparan sulfate proteoglycans, glypicans 1 and 5, the latter closely related to the primary defect. The level of secondary accumulations was associated with elevation of glypican, as seen by comparing brains of mice at different ages or with different mucopolysaccharide storage diseases. The MEC of an MPS IIIA mouse had the same intense immunostaining for glypican 1 and other markers as MPS IIIB, while MEC of MPS I and MPS II mice had weak staining, and MEC of an MPS VI mouse had no staining at all for the same proteins. A considerable amount of glypican was found in MEC of MPS IIIB mice outside of lysosomes. We propose that it is the extralysosomal glypican that would be harmful to neurons, because its heparan sulfate branches could potentiate the formation of Ptau and beta amyloid aggregates, which would be toxic as well as difficult to degrade.
Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-inAlzheimer mouse, PLB1.
Source
School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, United Kingdom. b.platt@abdn.ac.uk
Abstract
Late-stage neuropathological hallmarks of Alzheimer's disease (AD) are β-amyloid (βA) and hyperphosphorylated taupeptides, aggregated into plaques and tangles, respectively. Corresponding phenotypes have been mimicked in existing transgenic mice, however, the translational value of aggressive over-expression has recently been questioned. As controlled gene expression may offer animal models with better predictive validity, we set out to design a transgenic mouse model that circumvents complications arising from pronuclear injection and massive over-expression, by targeted insertion of human mutated amyloid and tau transgenes, under the forebrain- and neurone-specific CaMKIIα promoter, termed PLB1(Double). Crossing with an existing presenilin 1 line resulted in PLB1(Triple) mice. PLB1(Triple) mice presented with stable gene expression and age-related pathology of intra-neuronal amyloid and hyperphosphorylated tauin hippocampus and cortex from 6 months onwards. At this early stage, pre-clinical (18)FDG PET/CT imaging revealed cortical hypometabolism with increased metabolic activity in basal forebrain and ventral midbrain. Quantitative EEG analyses yielded heightened delta power during wakefulness and REM sleep, and time in wakefulness was already reliably enhanced at 6 months of age. These anomalies were paralleled by impairments in long-term and short-term hippocampal plasticity and preceded cognitive deficits in recognition memory, spatial learning, and sleep fragmentation all emerging at ∼12 months. These data suggest that prodromal AD phenotypes can be successfully modelled in transgenic mice devoid of fibrillary plaque or tangle development. PLB1(Triple) mice progress from a mild (MCI-like) state to a more comprehensive AD-relevant phenotype, which are accessible using translational tools such as wireless EEG and microPET/CT.
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