System In Alzheimer's Disease Research Articles

ALZHEIMER PATHOLOGY AND CHOLINESTERASES IN THE PRIMARY OLFACTORY GYRUS

Olfactory dysfunction frequently occurs in Alzheimer's disease (AD), often manifesting before cognitive symptoms. Early deposition of AD pathology is observed in regions of the primary olfactory system, including the anterior olfactory nucleus (AON). AD pathology has been described in the bulbar (olfactory bulb) and peduncular (olfactory tract) AON. However, limited studies have examined the cortical portion within the primary olfactory gyrus (POG). Furthermore, despite the importance of the cholinergic system in AD, cholinesterases have not been explored in this region. This study looks to expand upon the anatomical and cholinergic organization of the POG in the normal brain and to describe the neuropathological changes that occur in this region in AD. Fourteen (8 normal and 6 AD) brain tissue cases were obtained from the Maritime Brain Tissue Bank. The anatomical organization of POG relative to surrounding tissues was studied using Nissl staining. POG tissues were examined for the distribution of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity using histochemical techniques. β-amyloid (Aβ) plaques and tau neurofibrillary tangles (NFTs) were detected using immunohistochemistry. The abundance of AD pathology was measured using a semi-quantitative approach. The POG is comprised of cortical AON and olfactory tract, ventrally, and paleocortical olfactory area (OA), dorsally. Abundant AChE activity, associated with neurons and neuropil, was detected in the AON and OA, with very little activity noted in the olfactory tract. In contrast, BChE activity was associated with neurons and microglia in the AON and OA, while activity was prominent in the olfactory tract. The AON and OA, showed frequent deposition of cholinesterase-associated AD pathology, for both Aβ plaques and tau NFTs. Distribution of AD pathology revealed a specific laminar pattern within the OA. The abundance of BChE-associated AD pathology was greater than that associated with AChE in the POG. AChE and BChE activities in the normal POG recapitulated similar distributions in other cortical and subcortical brain regions. In AD, there was greater abundance of BChE-associated plaques in comparison to AChE-associated plaques in the POG. This suggests that BChE-associated pathology contributes to olfactory dysfunction in AD. Further studies are required to elucidate its significance.

Diagnostic accuracy of CSF neurofilament light chain protein in the biomarker-guided classification system for Alzheimer's disease

We assessed the diagnostic accuracy of cerebrospinal fluid (CSF) neurofilament light chain (NFL) protein in the classification of patients with Alzheimer's disease (AD) and cognitively healthy control individuals (HCs) and patients with frontotemporal dementia (FTD) as comparisons. Particularly, we tested the performance of CSF NFL concentration in differentiating patient groups stratified by fluid biomarker profiles, independently of the severity of cognitive impairment (mild cognitive impairment (MCI) and AD dementia individuals), using a biomarker-guided descriptive classification system for AD. CSF NFL concentrations were examined in a multicenter cross-sectional study of 108 participants stratified in AD pathophysiology-negative (both CSF tau and the 42-amino acid-long amyloid-beta (Aβ) peptide (Aβ1-42)) (n = 15), tau pathology-positive only (n = 15), Aβ pathology-positive only (n = 13), AD pathophysiology-positive (n = 33), FTD (n = 9) patients, and HCs (n = 23), according to the biomarker-based classification system. The performance of CSF NFL in discriminating AD pathophysiology-positive patients from HCs is fair, whereas the ability in differentiating tau-positive patients from HCs is poor. The classificatory performance in distinguishing AD pathophysiology-positive patients from FTD is unsatisfactory.

Enhanced Feedback-Related Negativity in Alzheimer's Disease.

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, results in the impairment of executive function, including that of performance monitoring. Feedback-related negativity (FRN) is an electrophysiological measure reflecting the activity of this monitoring system via feedback signals, and is generated from the anterior cingulate cortex. However, there have been no reports on FRN in AD. Based on prior aging studies, we hypothesized that FRN would decrease in AD patients. To assess this, FRN was measured in healthy individuals and those with AD during a simple gambling task involving positive and negative feedback stimuli. Contrary to our hypothesis, FRN amplitude increased in AD patients, compared with the healthy elderly. We speculate that this may reflect the existence of a compensatory mechanism against the decline in executive function. Also, there was a significant association between FRN amplitude and depression scores in AD, and the FRN amplitude tended to increase insomuch as the Self-rating Depression Scale (SDS) was higher. This result suggests the existence of a negative bias in the affective state in AD. Thus, the impaired functioning monitoring system in AD is a more complex phenomenon than we thought.

A second wind for the cholinergic system in Alzheimer's therapy.

Notwithstanding tremendous research efforts, the cause of Alzheimer's disease (AD) remains elusive and there is no curative treatment. The cholinergic hypothesis presented 35 years ago was the first major evidence-based hypothesis on the etiology of AD. It proposed that the depletion of brain acetylcholine was a primary cause of cognitive decline in advanced age and AD. It relied on a series of observations obtained in aged animals, elderly, and AD patients that pointed to dysfunctions of cholinergic basal forebrain, similarities between cognitive impairments induced by anticholinergic drugs and those found in advanced age and AD, and beneficial effects of drugs stimulating cholinergic activity. This review revisits these major results to show how this hypothesis provided the drive for the development of anticholinesterase inhibitor-based therapies of AD, the almost exclusively approved treatment in use despite transient and modest efficacy. New ideas for improving cholinergic therapies are also compared and discussed in light of the current revival of the cholinergic hypothesis on the basis of two sets of evidence from new animal models and refined imagery techniques in humans. First, human and animal studies agree in detecting signs of cholinergic dysfunctions much earlier than initially believed. Second, alterations of the cholinergic system are deeply intertwined with its reactive responses, providing the brain with efficient compensatory mechanisms to delay the conversion into AD. Active research in this field should provide new insight into development of multitherapies incorporating cholinergic manipulation, as well as early biomarkers of AD enabling earlier diagnostics. This is of prime importance to counteract a disease that is now recognized to start early in adult life.

Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity.

Recent genetic evidence supports a link between microglia and the complement system in Alzheimer's disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble β-amyloid (Aβ) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein-transgenic mice results in decreased, rather than increased, Aβ accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular Aβ by secreting enzymatic factors, including tissue plasminogen activator. Furthermore, a small molecule modulator of CR3 reduces soluble Aβ levels and Aβ half-life in brain interstitial fluid (ISF), as measured by in vivo microdialysis. These results suggest that CR3 limits Aβ clearance from the ISF, illustrating a novel role for CR3 and microglia in brain Aβ metabolism and defining a potential new therapeutic target in AD.

Different trajectories of decline for global form and global motion processing in aging, mild cognitive impairment and Alzheimer's disease

The visual processing of complex motion is impaired in Alzheimer's disease (AD). However, it is unclear whether these impairments are biased toward the motion stream or part of a general disruption of global visual processing, given some reports of impaired static form processing in AD. Here, for the first time, we directly compared the relative preservation of motion and form systems in AD, mild cognitive impairment, and healthy aging, by measuring coherence thresholds for well-established global rotational motion and static form stimuli known to be of equivalent complexity. Our data confirm a marked motion-processing deficit specific to some AD patients, and greater than any form-processing deficit for this group. In parallel, we identified a more gradual decline in static form recognition, with thresholds raised in mild cognitive impairment patients and slightly further in the AD group compared with controls. We conclude that complex motion processing is more vulnerable to decline in dementia than complex form processing, perhaps owing to greater reliance on long-range neural connections heavily targeted by AD pathology.

Involvement of GluN2B subunit containing N-methyl-d-aspartate (NMDA) receptors in mediating the acute and chronic synaptotoxic effects of oligomeric amyloid-beta (Aβ) in murine models of Alzheimer's disease (AD)

To elucidate whether a permanent reduction of the GluN2B subunit affects the pathology of Alzheimer's disease (AD), we cross-bred mice heterozygous for GluN2B receptors in the forebrain (hetGluN2B) with a mouse model for AD carrying a mutated amyloid precursor protein with the Swedish and Arctic mutation (mAPP) resulting in a hetGluN2B/mAPP transgenic. By means of voltage-sensitive dye imaging (VSDI) in the di-synaptic hippocampal pathway and the recording of field excitatory postsynaptic potentials (fEPSPs), hippocampal slices of all genotypes (WT, hetGluN2B, mAPP and hetGluN2B/mAPP, age 9–18 months) were tested for spatiotemporal activity propagation and long-term potentiation (LTP) induction. CA1-LTP induced by high frequency stimulation (HFS; 100 Hz/1s) was not different in all genotypes. Aβ1-42 (50 nM)-application reduced potentiation of fEPSP in WT and hetGluN2B/mAPP mice, LTP in mAPP and hetGluN2B mice was not affected. For VSDI a fast depolarization signal was evoked in the granule cell layer and propagation was analysed in hippocampal CA3 and CA1 region before and after theta stimulation (100pulses/5 Hz). LTP was not significantly different between all genotypes. In mAPP mice θ-stim produced an epileptiform activity reflected in a pronounced prolongation of the FDS compared to the other genotypes. In slices of hetGluN2B/mAPP and GluN2B mice, however, these parameters were similar to WT mice indicating a reversal effect of the attenuated GluN2B expression.The induction of a hetGluN2B mutation in the mAPP reversed some pathophysiological changes on hippocampal LTP and provide further evidence for the involvement of the glutamatergic system in AD and emphasize the GluN2B subunit as a potential target for AD treatment.

Noradrenergic Modulation of Cognition in Health and Disease.

Norepinephrine released by the locus coeruleus modulates cellular processes and synaptic transmission in the central nervous system through its actions at a number of pre- and postsynaptic receptors. This transmitter system facilitates sensory signal detection and promotes waking and arousal, processes which are necessary for navigating a complex and dynamic sensory environment. In addition to its effects on sensory processing and waking behavior, norepinephrine is now recognized as a contributor to various aspects of cognition, including attention, behavioral flexibility, working memory, and long-term mnemonic processes. Two areas of dense noradrenergic innervation, the prefrontal cortex and the hippocampus, are particularly important with regard to these functions. Due to its role in mediating normal cognitive function, it is reasonable to expect that noradrenergic transmission becomes dysfunctional in a number of neuropsychiatric and neurodegenerative diseases characterized by cognitive deficits. In this review, we summarize the unique role that norepinephrine plays in prefrontal cortical and hippocampal function and how its interaction with its various receptors contribute to cognitive behaviors. We further assess the changes that occur in the noradrenergic system in Alzheimer's disease, Parkinson's disease, attention-deficit/hyperactivity disorder, and schizophrenia and how these changes contribute to cognitive decline in these pathologies.

Targeting the guanine-based purinergic system in Alzheimer's disease.

Targeting the guanine-based purinergic system in Alzheimer's disease.

Extensive Association of Common Disease Variants with Regulatory Sequence.

Overlap between non-coding DNA regulatory sequences and common variant associations can help to identify specific cell and tissue types that are relevant for particular diseases. In a systematic manner, we analyzed variants from 94 genome-wide association studies (reporting at least 12 loci at p<5x10-8) by projecting them onto 466 epigenetic datasets (characterizing DNase I hypersensitive sites; DHSs) derived from various adult and fetal tissue samples and cell lines including many biological replicates. We were able to confirm many expected associations, such as the involvement of specific immune cell types in immune-related diseases and tissue types in diseases that affect specific organs, for example, inflammatory bowel disease and coronary artery disease. Other notable associations include adrenal glands in coronary artery disease, the immune system in Alzheimer’s disease, and the kidney for bone marrow density. The association signals for some GWAS (for example, myopia or age at menarche) did not show a clear pattern with any of the cell or tissue types studied. In general, the identified variants from GWAS tend to be located outside coding regions. Altogether, we have performed an extensive characterization of GWAS signals in relation to cell and tissue-specific DHSs, demonstrating a key role for regulatory mechanisms in common diseases and complex traits.

INVOLVEMENT OF CENTRAL OLFACTORY SYSTEM IN ALZHEIMER'S DISEASE AND MCI

INVOLVEMENT OF CENTRAL OLFACTORY SYSTEM IN ALZHEIMER'S DISEASE AND MCI

Association between naturally occurring anti-amyloid β autoantibodies and medial temporal lobe atrophy in Alzheimer's disease

BackgroundNaturally occurring autoantibodies against amyloid β (Aβ) peptide exist in the serum and cerebrospinal fluid (CSF) of healthy individuals. Recently, it was reported that administration of intravenous immunoglobulin at the...

Targeting copper(II)-induced oxidative stress and the acetylcholinesterase system in Alzheimer's disease using multifunctional tacrine-coumarin hybrid molecules

Alzheimer's disease is a multifactorial disease that is characterized mainly by Amyloid-β (A-β) deposits, cholinergic deficit and extensive metal (copper, iron)-induced oxidative stress. In this work we present details of the synthesis, antioxidant and copper-chelating properties, DNA protection study, cholinergic activity and amyloid-antiaggregation properties of new multifunctional tacrine-7-hydroxycoumarin hybrids. The mode of interaction between copper(II) and hybrids and interestingly, the reduction of Cu(II) to Cu(I) species (for complexes Cu-5e-g) were confirmed by EPR measurements. EPR spin trapping on the model Fenton reaction, using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, demonstrated a significantly suppressed formation of hydroxyl radicals for the Cu-5e complex in comparison with free copper(II). This suggests that compound 5e upon coordination to free copper ion prevents the Cu(II)-catalyzed decomposition of hydrogen peroxide, which in turn may alleviate oxidative stress-induced damage. Protective activity of hybrids 5c and 5e against DNA damage in a Fenton system (copper catalyzed) was found to be in excellent agreement with the EPR spin trapping study. Compound 5g was the most effective in the inhibition of acetylcholinesterase (hAChE, IC50=38nM) and compound 5b was the most potent inhibitor of butyrylcholinesterase (hBuChE, IC50=63nM). Compound 5c was the strongest inhibitor of A-β1–40 aggregation, although a significant inhibition (>50%) was detected for compounds 5b, 5d, 5e and 5g. Collectively, these results suggest that the design and investigation of multifunctional agents containing along with the acetylcholinesterase inhibitory segment also an antioxidant moiety capable of alleviating metal (copper)-induced oxidative stress, may be of importance in the treatment of Alzheimer's disease.

ChemInform Abstract: Structure of Amyloid Oligomers and Their Mechanisms of Toxicities: Targeting Amyloid Oligomers Using Novel Therapeutic Approaches

AbstractReview: 264 refs.

Mitochondrially-Derived Peptides as Defense Against Amyloid Protein Misfolding

The misfolding and aggregation of proteins is the pathological hallmark of amyloid diseases including Alzheimer's disease (AD), familial amyloid polyneuropathy, and type 2 diabetes mellitus (T2DM). Insofar as the misfolding process results in the formation of pathogenic species, inhibition of misfolding is thought to be a promising approach to the prevention of the aforementioned diseases. Mitochondrial dysfunction has been implicated in many amyloid diseases suggesting an important mitochondrial role. Humanin and its derivatives are a novel class of mitochondrially-derived peptides with insulin sensitizing activity and various cytoprotective effects in AD and other disease model systems. Here we tested whether humanin can promote health in misfolding diseases by acting as a molecular chaperone that prevents amyloid misfolding. We tested whether islet amyloid polypeptide (IAPP), a peptide that misfolds and causes toxicity in T2DM, would be responsive to humanin. Using thioflavin T fluorescence we found that substoichiometric concentrations of the humanin-S14G analogue (HNG) potently inhibit the misfolding of hIAPP. As assessed by circular dichroism, HNG prevents misfolding by maintaining hIAPP in a predominantly random coil structure in solution. Unexpectedly, site-directed spin labeling of HNG in concert with electron paramagnetic resonance (EPR) revealed that HNG is capable of forming higher order complexes. Ongoing investigation into the potency of these higher order structures will test whether they participate in the inhibition of IAPP misfolding. Finally HNG appears to have biological effects including a partial attenuation of IAPP-mediated cytotoxicity and a reversal of the increase in oxygen consumption seen when INS832/13 cells, a rodent insulinoma cell line, are challenged with IAPP. In summary our studies suggest the possibility that humanin, and perhaps other mitochondrially-derived peptides, have chaperone-like properties that could reverse the pathological processes involved in the development of T2DM.

Is the regulation of immune system in Alzheimer's disease effective?

Is the regulation of immune system in Alzheimer's disease effective?

The choroid plexus-cerebrospinal fluid interface in Alzheimer's disease: more than just a barrier.

The choroid plexus is a complex structure which hangs inside the ventricles of the brain and consists mainly of choroid plexus epithelial (CPE) cells surrounding fenestrated capillaries. These CPE cells not only form an anatomical barrier, called the blood-cerebrospinal fluid barrier (BCSFB), but also present an active interface between blood and cerebrospinal fluid (CSF). CPE cells perform indispensable functions for the development, maintenance and functioning of the brain. Indeed, the primary role of the choroid plexus in the brain is to maintain homeostasis by secreting CSF which contains different molecules, such as nutrients, neurotrophins, and growth factors, as well as by clearing toxic and undesirable molecules from CSF. The choroid plexus also acts as a selective entry gate for leukocytes into the brain. Recent findings have revealed distinct changes in CPE cells that are associated with aging and Alzheimer's disease. In this review, we review some recent findings that highlight the importance of the CPE-CSF system in Alzheimer's disease and we summarize the recent advances in the regeneration of brain tissue through use of CPE cells as a new therapeutic strategy.

Role of Lactobacillus plantarum MTCC1325 in membrane-bound transport ATPases system in Alzheimer's disease-induced rat brain.

Introduction: Alzheimer’s disease (AD) is a neurodegenerative disorder, clinically characterized by memory dysfunction and progressive loss of cognition. No curative therapeutic or drug is available for the complete cure of this disease. The present study was aimed to evaluate the efficacy of Lactobacillus plantarum MTCC1325 in ATPases activity in the selected brain regions of rats induced with Alzheimer’s. Methods: For the study, 48 healthy Wistar rats were divided into four groups: group I as control group, group II as AD model (AD induced by intraperitoneal injection of D-Galactose, 120 mg/kg body weight for 6 weeks), group III as normal control rats which were orally administered only with L. plantarum MTCC1325 for 60 days, and group IV where the AD-induced rats simultaneously received oral treatment of L. plantarum MTCC1325 (10ml/kg body weight, 12×108 CFU/mL) for 60 days. The well known membrane bound transport enzymes including Na+, K+-ATPases, Ca2+-ATPases, and Mg2+-ATPases were assayed in the selected brain regions of hippocampus and cerebral cortex in all four groups of rats at selected time intervals. Results: Chronic injection of D-Galactose caused lipid peroxidation, oxidative stress, and mitochondrial dysfunction leading to the damage of neurons in the brain, finally bringing a significant decrease (-20%) in the brain total membrane bound ATPases over the controls. Contrary to this, treatment of AD-induced rats with L. plantarum MTCC1325 reverted all the constituents of ATPase enzymes to near normal levels within 30 days. Conclusion: Lactobacillus plantarum MTCC1325 exerted a beneficial action on the entire ATPases system in AD-induced rat brain by delaying neurodegeneration.

Immunotherapies in Alzheimer's disease: Too much, too little, too late or off-target?

Years of research have highlighted the importance of the immune system in Alzheimer's disease (AD), a system that, if manipulated during strategic time windows, could potentially be tackled to treat this disorder. However, to minimize adverse effects, it is essential to first grasp which exact aspect of it may be targeted. Several clues have been collected over the years regarding specific immune players strongly modulated during different stages of AD progression. However, the inherent complexity of the immune system as well as conflicting data make it quite challenging to pinpoint a specific immune target in AD. In this review, we discuss immune-related abnormalities observed in the periphery as well as in the brain of AD patients, in relation to known risk factors of AD such as genetics, type-2 diabetes or obesity, aging, physical inactivity and hypertension. Although not investigated yet in clinical trials, C5 complement system component, CD40/CD40L interactions and the CXCR2 pathway are altered in AD patients and may represent potential therapeutic targets. Immunotherapies tested in a clinical context, those aiming to attenuate the innate immune response and those used to facilitate the removal of pathological proteins, are further discussed to try and understand the causes of the limited success reached. The prevailing eagerness to move basic research data to clinic should not overshadow the fact that a careful preclinical characterization of a drug is still required to ultimately improve the chance of clinical success. Finally, specific elements to consider prior to initiate large-scale trials are highlighted and include the replication of preclinical data, the use of small-scale human studies, the sub-typing of AD patients and the determination of pharmacokinetic and pharmacodynamics parameters such as brain bioavailability and target engagement.

Resveratrol: More than a phytochemical

In recent years, alternative and complementary medicine including the plant-based drugs with antioxidant and neuroptotective effects has attracted a growing interest. Resveratrol, a polyphenolic compound which is found in various plant species, has emerged as a promising nutraceutical with therapeutic potentials in neuropsychiatric, cardiometabolic and cancer diseases, also aging. The abundance of research providing promising findings about the multi-spectrum therapeutic applications of resveratrol and its encouraging potential to treat or prevent chronic and age-related disorders has raised a considerable number of clinical trials. Recently, resveratrol is implicated the biology of nerve growth factor (NGF), a critical player in the maintenance of neuronal growth and function. Furthermore, resveratrol affects the endocannabinoid signalling (eCBs) which exerts modulatory effects in the survival signalling pathways, neural plasticity, and a variety of neuroinflammatory and neurodegenerative processes. The therapeutic effects of this ubiquitous signalling system in Alzheimer’s disease, epilepsy, multiple sclerosis, mood and movement disorders, spinal cord injury, and stroke have been well-documented. In the present review, the implication of NGF and eCBs in the mechanism of action of resveratrol, that may be of therapeutic significance in neurological and non-neurological disorders, is highlighted. Biomed Rev 2015; 26: 13-21.