Current Alzheimer Research - Volume 10, Issue 8, 2013

The β-secretase, BACE1, generates β-amyloid (Aβ), a major hallmark of Alzheimer's disease (AD) pathology. The elevation of BACE1 levels in brains of AD patients may play a role in initiating or propagating disease. BACE1 levels are increased under low energy or low oxygen conditions, which may occur in individuals with impaired circulation in the brain. We compared levels of BACE1 in the brains of aged, non-demented individuals with high or low levels of atherosclerosis in the circle of Willis, and found that while there is no change in BACE1, Aβ42 levels are elevated in the high atherosclerosis group.

Context: Alzheimer's disease (AD) is usually only diagnosed many years after pathology begins. Earlier detection would allow emerging interventions to have a greater chance to preserve healthy brain function. A rare form of Alzheimer's disease, caused by autosomal-dominant mutations, affects carriers with 100% certainty and at a younger age specific to their mutation. Studying families with these mutations allows a unique investigation of the temporal sequence of biomarker changes in Alzheimer's disease. Objective: To determine whether the pupil flash response (PFR), previously reported to be altered in sporadic Alzheimer's disease, is different in pre-symptomatic mutation carriers. Design: Researchers blinded to participant mutation status collected pupil response data from cognitively normal participants in the Dominantly Inherited Alzheimer's Network (DIAN) Study during 2010-2011. Setting: The pupil response was examined at the McCusker Alzheimer's Research Foundation in Perth, Western Australia. Participants: Participants were from a single family harboring an Amyloid-Beta Precursor Protein genetic mutation (APPGlu693Gln). Six carriers and six non-carriers were available for pupil testing (age 43.0±8.3 years old, 2 males and 10 females, 4 with hypertension). Main Outcome Measure: Pupil response parameter comparison between mutation carriers and non-carriers. Results: 75% recovery time was longer in mutation carriers (p<0.0003, ROC AUC 1.000, Sensitivity 100%, Specificity 100%) and percentage recovery 3.5 seconds after stimulus was less in mutation carriers (p<0.006, ROC AUC 1.000, Sensitivity 100%, Specificity 100%). Conclusions: PFR changes occur pre-symptomatically in autosomal dominant AD mutation carriers, supporting further investigation of PFR for early detection of AD.

Amyloid beta (Aβ) aggregation and deposition is a key pathological hallmark of AD. Growing evidence suggests that neurotoxicity of this peptide is related to the formation of toxic oligomeric aggregates. Therefore, a deeply investigated therapeutic strategy comes at present from blocking the formation of these species to non-toxic aggregates. Among other considered strategies, the multi-target approach has been proposed as a more suitable potential therapy, precisely due to the multifactorial nature of AD. In this context, we recently identified ASS234, a novel compound that possesses a significant multipotent profile since it is able to inhibit cholinesterase and monoamine oxidase enzymes as well as to interfere in Aβ aggregation process. In this work, we investigated more in detail the effects of ASS234 on Aβ aggregation and toxicity in vitro as well as we explored its ability to penetrate to the CNS. We report that ASS234 inhibited Aβ1-42 self-aggregation more efficiently than that of Aβ1-40, limiting the formation of fibrillar and oligomeric species. Additionally, ASS234 completely blocked the aggregation mediated by AChE of both Aβ1-42 and Aβ1-40, showing a dual binding site to AChE. Interestingly, ASS234 significantly reduced Aβ1-42-mediated toxicity in SH-SY5Y human neuroblastoma cells through the prevention of the mitochondrial apoptosis pathway activation. Also importantly, we observed a significant ability of ASS234 to capture free-radical species in vitro as well as a potent effect in preventing the Aβ1-42-induced depletion of antioxidant enzymes (catalase and SOD-1). Finally, we report the capability of ASS234 to cross the bloodbrain barrier. Overall, our in vitro results show that ASS234 may have an impact on different processes involved in AD pathogenesis and provide evidences that it has encouraging attributes as a therapeutic lead compound.

A key feature of Alzheimer's disease (AD) is deposition of extracellular amyloid plaque comprised chiefly of the amyloid β (Aβ) peptide. Studies of Aβ have shown that it may be catabolized by proteolysis or cleared from brain via members of the low-density lipoprotein receptor family. Alternatively, Aβ can undergo a conformational transition from α-helix to β-sheet, a conformer that displays a propensity to self-associate, oligomerize and form fibrils. Furthermore, β- sheet conformers catalyze conversion of other α-helical Aβ peptides to β-sheet, feeding the oligomer and fibril assembly process. A factor that influences the fate of Aβ in the extracellular space is apolipoprotein (apo) E. Polymorphism at position 112 or 158 in apoE give rise to three major isoforms. One isoform in particular, apoE4 (Arg at 112 and 158), has generated considerable interest since the discovery that it is the major genetic risk factor for development of late onset AD. Despite this striking correlation, the molecular mechanism underlying apoE4's association with AD remains unclear. A tertiary structural feature distinguishing apoE4 from apoE2 and apoE3, termed domain interaction, is postulated to affect the conformation and orientation of its&apos two independently folded domains. This feature has the potential to influence apoE4's interaction with Aβ, its sensitivity to proteolysis or its lipid accrual and receptor binding activities. Thus, domain interaction may constitute the principal molecular feature of apoE4 that predisposes carriers to late onset AD. By understanding the contribution of apoE4 to AD at the molecular level new therapeutic or prevention strategies will emerge.

In Alzheimer's disease (AD), neurofibrillary degeneration in the hemispheres starts in the limbic and paralimbic regions prior to those in the isocortical ones but factors determining the progression of these changes are unknown. Previous studies have shown that migration of extracellular substances (volume transmission) driven by arterial pulse pressure waves from the cerebrospinal fluid (CSF) towards the brain parenchyma occurs earlier in these limbic and paralimbic cortices located around the basal cisterns containing the proximal segments of the main hemispheric arteries than in the isocortex. Considering this similarity, the aim of our study was to examine the relation between the proximal segments of the main hemispheric arteries and the development and spread of neurofibrillary tangles (NFTs) in limbic and early isocortical Braaks' stages. Blocks following proximosdistal levels of the anterior and middle cerebral arteries containing areas of the cingulate and insular cortices, respectively, were dissected and NFTs were counted. In both regions, the density of NFTs decreased in parallel with the proximodistal segments of the accompanying arteries. Our results show that neurofibrillary degeneration in AD is related to the proximodistal levels of the main hemispheric arteries and raise the possibility that this effect is mediated by volume transmission from the CSF into the brain.

The activities of CDK5 and p35 are thought to be important in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). We studied the effect of p35 deletion in Tg2576 mice, which is an AD animal model. To obtain the desired mice, we crossed p35-/- with Tg2576 mice. The resulting p35-/-/Tg2576 (KO/Tg) mice displayed higher mortality rates and exhibited impaired spatial learning and memory at 6 months of age. Using immunohistochemical and biochemical approaches, we observed a reduction in the expression of pre- and post-synaptic markers such as NMDAR1, synaptophysin and GluR1. In addition, the intensity of MAP-2-positive dendrites extending from neuronal cell bodies was significantly decreased in KO/Tg mice compared with KO/WT and WT/Tg mice. We also detected increased neuronal cell death in the hippocampus, along with thinned and collapsed morphological changes in the alveus region and a dramatic increase in the number of microglial cells. Microglial infiltration in the hippocampus could result in the increased secretion of the soluble high mobility group box-1 protein (HMGB-1). The secretion of HMGB-1 is increased by Aβ, and secretion of HMGB-1 promotes neuronal cell death. Moreover, we found that HMGB-1 secretion induced by Aβ in KO/Tg mice gave rise to ER-mediated cell death. In summary, during the stages of KO/Tg mice model, the microglial infiltration and secretion of soluble HMGB-1 were significantly increased in the hippocampus. These conditions promote neuronal death, synaptic destruction and behavioral deficits.

Background: Although it is now evident that normal cognition can occur despite significant AD pathology, few studies have attempted to characterize this discordance, or examine factors that may contribute to resilient brain aging in the setting of AD pathology. Methods: More than 2,000 older persons underwent annual evaluation as part of participation in the Religious Orders Study or Rush Memory Aging Project. A total of 966 subjects who had brain autopsy and comprehensive cognitive testing proximate to death were analyzed. Resilience was quantified as a continuous measure using linear regression modeling, where global cognition was entered as a dependent variable and global pathology was an independent variable. Studentized residuals generated from the model represented the discordance between cognition and pathology, and served as measure of resilience. The relation of resilience index to known risk factors for AD and related variables was examined. Results: Multivariate regression models that adjusted for demographic variables revealed significant associations for early life socioeconomic status, reading ability, APOE-ε4 status, and past cognitive activity. A stepwise regression model retained reading level (estimate = 0.10, SE = 0.02; p< 0.0001) and past cognitive activity (estimate = 0.27, SE = 0.09; p = 0.002), suggesting the potential mediating role of these variables for resilience. Conclusions: The construct of resilient brain aging can provide a framework for quantifying the discordance between cognition and pathology, and help identify factors that may mediate this relationship.

At present, the etiology of Alzheimer’s disease (AD) is still unclear, but both genetic and non-genetic factors are thought to take part in the etiopathogenesis of AD. Epidemiologic researches revealed that genetic factors played a decisive role in the development of both early-onset AD (EOAD) and late-onset AD (LOAD). The mutations in APP, PSEN1 and PSEN2 are inherited in a Mendelian fashion and directly lead to the EOAD, while recent genome-wide association studies have identified numbers of risky genes, which influences the susceptibility to LOAD. Although genetic factors are inherited and fixed, non-genetic factors, such as occupational exposures (exposure to pesticides, electromagnetic fields, organic solvents and volatile anesthetics), pre-existing medical conditions (cerebrovascular disease, hypertension, diabetes, dyslipidemia, traumatic brain injury, depression and cancer) and lifestyle factors (smoking, consumptions of alcohol and coffee, body mass index, physical activity and cognitive activity), are partly environmentally-determined. Timely interventions targeted at these non-genetic risk factors may offer opportunities for prevention and treatment of AD. In the future, more high-quality and large-sample epidemiologic studies are needed to identify risk factors for AD, and the interaction models between genetic and non-genetic risk factors required further investigation. In addition, public health campaigns targeted at modification of non-genetic risk factors should be developed among population at high risk of AD.

The aging process in the hippocampus is associated with aberrant epigenetic marks, such as DNA methylation and histone tail alterations. Recent evidence suggests that caloric restriction (CR) can potentially delay the aging process, while upregulation of antioxidants may also have a beneficial effect in this respect. We have recently observed that CR attenuates age-related changes in the levels of the epigenetic molecules DNA methyltransferase 3a, 5-methylcytidine (5- mC) and 5-hydroxymethylcytosine in the mouse hippocampus while overexpression of the antioxidant Cu/Zn superoxide dismutase 1 (SOD1) does not. However, the impact of aging on the levels of histone-modifying enzymes such as histone deacetylase 2 (HDAC2) in the hippocampus has not been studied in much detail. Here, we investigated immunoreactivity (IR) of HDAC2 in three subregions of the hippocampus (dentate gyrus, CA3 and CA1-2) of mice taken from large cohorts of aging wild-type and transgenic mice overexpressing normal human SOD1, which were kept under normal diet or CR from weaning onwards. Independent from the genotype, aging (between 12 and 24 months) increased levels of HDAC2 IR in the hippocampus. Moreover, CR prevented this age-related increase, particularly in the CA3 and CA1-2 subregions, while SOD1 overexpression did not. Quantitative image analyses showed that HDAC2 IR correlated positively with 5-mC IR while these markers were shown to colocalize in the nucleus of hippocampal cells. Together with recent literature reports, these findings suggest that altered levels of epigenetic regulatory proteins including HDAC2 regulate age-related changes in the mouse hippocampus and that CR may prevent these age-related changes.

The aim of this review is to summarize the current magnetic resonance imaging (MRI) variants applied on the studies of Alzheimer's disease (AD). Experimental findings, advantages and disadvantages, and the prospect of every individual technique will be presented. MRI can be used to investigate the change of the brain in terms of volume, function, white matter track orientation and even mechanical properties and metabolic concentration.Results from volumetric and morphological analysis indicated that the hippocampus reduced by approximately 18%-24% or 3%-4% annually. Functional MRI (fMRI) detected the blood oxygen level dependent (BOLD) signaland suggested thatmedial temporal lobe (MTL) such as hippocampus and entorhinal cortex reduced at the early stage of AD, and frontal, temporal, and parietal cortices at the later stage. In diffusion tensor imaging (DTI), the white matter fiber track integrity is measured but the results are inconsistent. Besides,magnetic resonance spectroscopy (MRS), chemical shift imaging (CSI), arterial spin labeling (ASL), magnetic resonance elastography (MRE) and susceptibility weighted imaging (SWI) will also be included in this review.

Alzheimer´s disease (AD) is a progressive neurodegenerative dementia which currently represents one of the biggest threats for the human kind. The cure is still unknown and various hypotheses (cholinergic, amyloidal, oxidative, vascular etc.) are investigated in order to understand the pathophysiology of the disease and on this basis find an effective treatment. Tacrine, the first approved drug for the AD disease treatment, has been reported to be a multitargeted drug, however it was withdrawn from the market particularly due to its hepatotoxicity. Its derivative 7-methoxytacrine (7- MEOTA) probably due to the different metabolization does not exert this side effect. The aim of our study was to compare these two cholinesterase inhibitors from various, mainly cholinergic, points of view relevant for a potential AD drug. We found that 7-MEOTA does not fall behind its more well-known parent compound – tacrine. Furthermore, we found, that 7-MEOTA exerts better properties in most of the tests related to a possible AD treatment. Only the pharmacokinetics and a higher acetylcholinesterase and butyrylcholinesterase inhibitory potency would slightly give advantages to tacrine over 7-MEOTA, but concerning its lower toxicity, better antioxidant properties, interaction with muscarinic and nicotinic receptors and “safer” metabolization provide strong evidence for reconsider 7-MEOTA and its derivatives as candidate molecules for the treatment of AD.