Current Alzheimer Research - Volume 10, Issue 4, 2013

There is good epidemiological evidence that vascular disease predisposes to cognitive decline and dementia. The impact of vascular disease on dementia is likely to increase further because of the poor diagnosis and management of vascular risk factors, the increase in life expectancy, and the improved survival following major cardiovascular events, e.g. acute stroke. It is estimated that the adequate management of vascular risk factors, with pharmacological and/or nonpharmacological interventions, might result in a 50% reduction in the forecasted dementia prevalence. The exact mechanisms by which vascular risk factors and vascular disease adversely affect brain function remain unclear, but it is hypothesized that endothelial dysfunction plays an important role. Reduced synthesis and availability of endothelial nitric oxide (NO) may contribute to the development of dementia by at least two mechanisms: 1) favoring the onset and progression of atherosclerosis, vasoconstriction, and impaired cerebral blood flow regulation; and 2) reduced neuroprotection. Several studies have shown that asymmetric dimethylarginine (ADMA), an endogenous methylated form of the amino acid L-arginine, inhibits NO synthesis and favors oxidative stress and vascular damage. Unlike NO, ADMA concentrations are relatively stable and can be accurately measured in plasma. There is good evidence that higher plasma ADMA concentrations favor atherosclerosis and independently predict adverse cardiovascular and cerebrovascular outcomes in several patient groups. ADMA might represent a unifying pathophysiological pathway linking the presence of vascular risk factors with the onset and progression of cognitive decline and dementia. This review discusses the biological role of ADMA, its potential contribution to the onset and progression of dementia through vascular disease and atherosclerosis, the available evidence linking ADMA with cognitive impairment and dementia, and the strategies to characterize the predictive role of ADMA in cognitive impairment in epidemiological studies. Therapeutic implications and suggestions for future research directions are also discussed.

The objective of this work was to improve the clinical diagnosis of Alzheimer's disease (AD) by proposing a simple decision tree based on three major biomarkers of AD found in the cerebrospinal fluid (CSF): amyloid peptide Aβ1- 42, total Tau (t-Tau) and Tau phosphorylated at Thr181 (p-Tau). Two consecutive cohorts comprising 548 patients in total were recruited by the Memory and Neurology Clinics at Lille University Hospital (France). These included 293 patients with AD, 171 patients with other dementias and 84 healthy controls. All patients underwent lumbar puncture for the assessment of CSF concentrations of Aβ1-42, t-Tau and p-Tau. International criteria for dementias were used for diagnosis by investigators blind to CSF test results. To identify the combination of biomarkers that best predicted the 3 diagnoses, we used the CHAID decision tree method with the first cohort. Our analysis yielded a two-step decision tree, with a first stratification step based on the Aβ1–42/p-Tau ratio of the CSF, and a second step based on CSF p-Tau concentrations. The second cohort was then used to determine the power (0.618), sensitivity (82%) and specificity (81%) of this tree in AD diagnosis. These were found to be at least as high as those of other known algorithms based on the three CSF biomarkers, Aβ1-42, t-Tau and p-Tau. For the first time, diagnostic rules for AD based on CSF variables were compared in a single study. Our findings indicate that the measurement of Aβ1-42 and p-Tau levels in the CSF is sufficient to diagnose AD.

A large body of evidences obtained in human and animal brain tissue suggest a role of oxidative stress (OxS) in the pathogenesis of late onset Alzheimer's disease (LOAD); on the contrary, data on peripheral markers of OxS in LOAD are still controversial. We evaluated the serum levels of products of lipid peroxidation, hydroperoxides, advanced oxidation protein products, total and residual antioxidant power, thiols, and uric acid in a sample of 334 older individuals: 101 LOAD patients, 134 patients with mild cognitive impairment (MCI), and 99 controls. At univariate analysis, serum hydroperoxides were higher while residual antioxidant power was lower in MCI and LOAD compared with in controls. By multivariate logistic regression analysis we found that, compared with controls, high levels (over median value) of serum hydroperoxides were independently associated with an increase in the likehood of having MCI (Odd Ratio: 2.59, 95% Confidence Interval: 1.08-6.21) or LOAD (OR: 4.09, 95%CI: 1.36-11.81). Furthermore, low levels of residual antioxidant power (below the median value) were associated with increased risk of having MCI (OR: 3.97, 95% CI: 1.62-9.72), but not dementia (OR: 2.31, 95%CI: 0.83-6.63). Our study suggests that a systemic redox-imbalance leading to OxS might be associated not only with LOAD but also with MCI.

Semantic memory decline has been found in Mild Cognitive Impairment (MCI). In this study performance on a range of semantic tasks and structural brain patterns were examined in a group of MCI patients. Fourteen MCI and sixteen healthy elderly controls underwent semantic memory assessment and MRI brain scanning. The cognitive battery included visual naming and naming from definition tasks for objects, actions and famous people, semantic fluency for animals, fruits, tools, furniture, singers, politicians, actions, word-association task for early and late acquired words and a reading task. MCI patients performed worse on semantic fluency in all categories except for tools, produced a smaller number of words associated with early acquired nouns and a smaller total number of word-associations. Patients scored more poorly in all tasks of naming, naming of famous people, overall reading and reading of famous people's names. MCIs had fewer correct immediate recalls and more correct responses with cue in famous people naming, made more errors in naming and in the naming from definition task for famous people. Grey matter reduction in parahippocampus, frontal and cingulate cortices and amygdala was found in the MCI sample when compared with controls. Patients presented a different pattern of brain areas correlated with semantic tasks from that seen in controls, with more extensive involvement of subcortical regions in semantic fluency and word-association and more contribution of frontal than temporo-parietal areas in visual naming. This evidence suggests a reorganization of cortical associations of semantic processes in MCI that, following damage in the semantic circuit, explains its progressive breakdown.

The Tg2576 mouse, which carries the Swedish mutant form of human β-amyloid precursor protein (hAPPswe), develops Alzheimer's Disease (AD)-like phenotype (synaptic pathology, cognitive impairment and β amyloid -Aβ- plaques.) in the absence of significant neuronal loss. We have analyzed the hippocampal proteome of Tg2576, focusing on changes at 7 months of age, when Aβ levels begin to increase but cognitive symptoms are still not evident, and at 16 months, when most AD-like features are manifested. Proteins differentially expressed with respect to wild-type animals were grouped according to their biological function and assessed in the context of AD. Metabolic enzymes, propionyl- CoA carboxylase, which has not been previously related to AD, and glutamine synthetase, which is a key enzyme for ammonium removal, were among deregulated proteins. Mitochondria of young animals have to cope with the metabolic stress and elevated ATP demand caused by overexpression of hAPPswe. Significantly, a large number of mitochondrial proteins (16, 28% of the total) were deregulated in young Tg2576 mice and seven of them were found at normal levels in aged animals. Mitochondrial dysfunction in 7-month-old mice was confirmed by reduction in the inner membrane integrity and increase in the activity of cytochrome c oxidase. The proteome analysis indicates that mitochondrial and overlapping metabolic alterations are adaptive upon aging, and may explain the synaptic pathology and cognitive impairment in the absence of neuronal loss. Animal models such as 7-month-old Tg2576 mice and tools to investigate synaptic alterations before appearance of neuronal death may help in understanding the pathological mechanisms occurring at early stages of AD.

This study aimed to show that the rat model of sporadic Alzheimer's disease (sAD) generated by the intracerebroventricular (icv) injection of a sub-diabetogenic dose of streptozotocin (icvSTZ) is characterized by brain mitochondrial abnormalities. Three-month-old male Wistar rats were investigated 5 weeks after a single bilateral icv injection of STZ (3mg/ Kg) or vehicle. icvSTZ administration induced a decrease in brain weight and cognitive decline, without affecting blood glucose levels. icvSTZ administration also resulted in a significant increase in hippocampal amyloid beta peptide 1-42 (Aβ1-42) levels as well as in cortical and hippocampal hyperphosphorylated tau protein levels. Brain mitochondria from icvSTZ rats revealed deficits in their function, as shown by a decrease in mitochondrial transmembrane potential, repolarization level, ATP content, respiratory state 3, respiratory control ratio and ADP/O index and an increase in lag phase of repolarization. Mitochondria from icvSTZ rats also displayed a decrease in pyruvate and α-ketoglutarate dehydrogenases and cytochrome c oxidase activities and an increase in the susceptibility to calcium-induced mitochondrial permeability transition. An increase in hydrogen peroxide and lipid peroxidation levels and a reduction in glutathione content were also observed in mitochondria from icvSTZ rats. These results demonstrate that the insulin-resistant brain state that characterizes this rat model of sAD is accompanied by the occurrence of mitochondrial abnormalities reinforcing the validity of this animal model to study sAD pathogenesis and potential therapies.

Stress has been described as a risk factor for the development of Alzheimer´s disease (AD). In the present work we aim to study the validity of an experimental model of neonatal chronic stress in order to recapitulate the main hallmarks of AD. Male Wistar rats that were separated daily from the dam during the first 3 weeks of life (maternal separation, MS) showed in adulthood cognitive deficits novel object recognition test. In the hippocampus of MS rats, increases in both Aβ40 and Aβ42 levels, the principal constituent of amyloid plaques observed in AD, were accompanied by increased expression of the cleaving enzyme BACE1. Hyperphosphorylation of Tau associated to increased activation of the tau kinase JNK1 was also found. Decreased cell number in the hippocampus was observed in stressed rats, as a consequence of both decreased cell proliferation and increased apoptotic death. Decreases in BDNF and in the synaptic markers synaptophysin and PSD-95 were also found in MS rats. All these effects could be related to an HPA axis hyperactivity, as reflected in significant increases in corticosterone levels and decreases in glucocorticoid receptor expression. Further, SHSY5Y neuroblastoma cells treated with corticosterone showed increased BACE1, pTau and pJNK1 expression. In addition, venlafaxine, an antidepressant able to modulate HPA axis activity, reversed all the above cited deleterious effects of chronic stress, both in vivo and in vitro. It is proposed that the MS model can be considered as an appropriate experimental model for the study of sporadic AD.

Autophagy plays an important role in Alzheimer's disease (AD). It has been reported that autophagic flux is altered in patients with AD, and application of the autophagy enhancer rapamycin may alleviate the cognitive impairment and amyloid-β (Aβ) neuropathology in transgenic animal model of AD. Since rapamycin is also an immune suppressor, there is a concern that long-term use of rapamycin may bring severe unwanted side effects. The aim of this study is to test if carbamazepine (CBZ), an anti-epileptic drug that has a potent autophagy enhancement effect, has anti-AD effects in APPswe/PS1deltaE9 transgenic mice model of AD. We found that APPswe/PS1deltaE9 mice display increased autophagic activity accompanied by decreased mTOR activity. After three months treatment with CBZ in the APPswe/PS1deltaE9 mice, we demonstrated that the spatial learning and memory deficits in these mice are significantly alleviated. We also documented that the cerebral amyloid plaque burden and Aβ42 levels in these mice are significantly reduced. Furthermore, we showed that CBZ significantly enhances the autophagic flux in the APPswe/PS1deltaE9 mice which is unlikely via mTOR-dependent autophagy pathway. These data suggest that long-term CBZ treatment may have a protective effect in AD mouse model possibly through enhancing the autophagic flux.

Deposition of amyloid-β (Aβ) peptides in the brain is a central event in the pathogenesis of Alzheimer's disease (AD), which makes Aβ peptides a crucial target for therapeutic intervention. Significant efforts have been made towards the development of ligands that bind to Aβ peptides with a goal of early detection of amyloid aggregation and the neutralization of Aβ toxicity. Short single-stranded oligonucleotide aptamers bind with high affinity and specificity to their targets. Aptamers that specifically bind to Aβ monomers, specifically the 40 and 42 amino acid species (Aβ1-40 and Aβ1- 42), fibrils and plaques have a great potential for diagnostic applications and the treatment of AD. Herein, we review the aptamers that bind to the various forms of Aβ peptides for use in diagnosis and to inhibit plaque formation.