Early Symptoms Of Alzheimer's Disease Research Articles

Marine-derived Compounds: A Powerful Platform for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a debilitating form of dementia that primarily affects cholinergic neurons in the brain, significantly reducing an individual's capacity for learning and creative skills and ultimately resulting in an inability to carry out even basic daily tasks. As the elderly population is exponentially increasing, the disease has become a significant concern for society. Therefore, neuroprotective substances have garnered considerable interest in addressing this universal issue. Studies have shown that oxidative damage to neurons contributes to the pathophysiological processes underlying AD progression. In AD, tau phosphorylation and glutamate excitotoxicity may play essential roles, but no permanent cure for AD is available. The existing therapies only manage the early symptoms of AD and often come with numerous side effects and toxicities. To address these challenges, researchers have turned to nature and explored various sources such as plants, animals, and marine organisms. Many historic holy books from different cultures emphasize that adding marine compounds to the regular diet enhances brain function and mitigates its decline. Consequently, researchers have devoted significant time to identifying potentially active neuroprotective substances from marine sources. Marine-derived compounds are gaining recognition due to their abundant supply of diverse chemical compounds with biological and pharmacological potential and unique mechanisms of action. Several studies have reported that plants exhibit multitarget potential in treating AD. In light of this, the current study focuses on marine-derived components with excellent potential for treating this neurodegenerative disease.

The features analysis of hemoglobin expression on visual information transmission pathway in early stage of Alzheimer’s disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized primarily by cognitive impairment. The motivation of this paper is to explore the impact of the visual information transmission pathway (V–H pathway) on AD, and the following feature were observed: Hemoglobin expression on the V–H pathway becomes dysregulated as AD occurs so as to the pathway becomes dysfunctional. According to the feature, the following conclusion was proposed: As AD occurs, abnormal tau proteins penetrate bloodstream and arrive at the brain regions of the pathway. Then the tau proteins or other toxic substances attack hemoglobin molecules. Under the attack, hemoglobin expression becomes more dysregulated. The dysfunction of V–H pathway has an impact on early symptoms of AD, such as spatial recognition disorder and face recognition disorder.

The important role of glial transmitters released by astrocytes in Alzheimer's disease: A perspective from dynamical modeling.

This paper aims to establish a coupling model of neuronal populations and astrocytes and, on this basis, explore the possible mechanism of electroencephalography (EEG) slowing in Alzheimer's disease (AD) from the viewpoint of dynamical modeling. First and foremost, excitatory and inhibitory time constants are shown to induce the early symptoms of AD. The corresponding dynamic nature is mainly due to changes in the amplitude and frequency of the oscillatory behavior. However, there are also a few cases that can be attributed to the change of the oscillation mode caused by the limit cycle bifurcation and birhythmicity. Then, an improved neural mass model influenced by astrocytes is proposed, considering the important effects of glutamate and adenosine triphosphate (ATP) released by astrocytes on the synaptic transmission process reported in experiments. The results show that a dysfunctional astrocyte disrupts the physiological state, causing three typical EEG slowing phenomena reported clinically: the decreased dominant frequency, the decreased rhythmic activity in the α band, and the increased rhythmic activity in the δ+θ band. In addition, astrocytes may control AD when the effect of ATP on synaptic connections is greater than that of glutamate. The control rate depends on the ratio of the effect of glutamate on excitatory and inhibitory synaptic connections. These modeling results can not only reproduce some experimental and clinical results, but, more importantly, may offer a prediction of some underlying phenomena, helping to inspire the disease mechanisms and therapeutic methods of targeting astrocytes.

Prefrontal parvalbumin interneurons deficits mediate early emotional dysfunction in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease and has an insidious onset. Exploring the characteristics and mechanism of the early symptoms of AD plays a critical role in the early diagnosis and intervention of AD. Here we found that depressive-like behavior and short-term spatial memory dysfunction appeared in APPswe/PS1dE9 mice (AD mice) as early as 9-11 weeks of age. Electrophysiological analysis revealed excitatory/inhibitory (E/I) imbalance in the prefrontal cortex (PFC). This E/I imbalance was induced by significant reduction in the number and activity of parvalbumin interneurons (PV+ INs) in this region. Furthermore, optogenetic and chemogenetic activation of residual PV+ INs effectively ameliorated depressive-like behavior and rescued short-term spatial memory in AD mice. These results suggest the PFC is selectively vulnerable in the early stage of AD and prefrontal PV+ INs deficits play a key role in the occurrence and development of early symptoms of AD.

Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice.

Age-related neurodegenerative diseases (NDDs) are associated with the aggregation and propagation of specific pathogenic protein species (e.g., Aβ, α-synuclein). However, whether disruption of synaptic homeostasis results from protein misfolding per se rather than accumulation of a specific rogue protein is an unexplored question. Here, we show that error-prone translation, with its frequent outcome of random protein misfolding, is sufficient to recapitulate many early features of NDDs, including perturbed Ca2+ signaling, neuronal hyperexcitability, and mitochondrial dysfunction. Mice expressing the ribosomal ambiguity mutation Rps9 D95N exhibited disrupted synaptic homeostasis resulting in behavioral changes reminiscent of early Alzheimer disease (AD), such as learning and memory deficits, maladaptive emotional responses, epileptiform discharges, suppressed circadian rhythmicity, and sleep fragmentation, accompanied by hippocampal NPY expression and cerebral glucose hypometabolism. Collectively, our findings suggest that random protein misfolding may contribute to the pathogenesis of age-related NDDs, providing an alternative framework for understanding the initiation of AD.

Early memory impairment is accompanied by changes in GluA1/p-GluA1 in APP/PS1 mice.

Exploring the neurobiological mechanisms of early AD damage Background: The early diagnosis of Alzheimer's disease (AD) has a very important impact on the prognosis of AD. However, the early symptoms of AD are not obvious and difficult to diagnose. Existing studies have rarely explored the mechanism of early AD. AMPARs are early important learning memory-related receptors. However, it is not clear how the expression levels of AMPARs change in early AD. We explored learning memory abilities and AMPAR expression changes in APP/PS1 mice at 4 months, 8 months, and 12 months. We used the classic Morris water maze to explore the learning and memory impairment of APP/PS1 mice and used western blotting to explore the changes in AMPARs in APP/PS1 mice. We found that memory impairment occurred in APP/PS1 mice as early as 4 months of age, and the impairment of learning and memory gradually became serious with age. The changes in GluA1 and p-GluA1 were most pronounced in the early stages of AD in APP/PS1 mice. Our study found that memory impairment in APP/PS1 mice could be detected as early as 4 months of age, and this early injury may be related to GluA1.

Targeting autophagy as a therapeutic strategy to prevent dopamine neuron loss in early stages of Alzheimer disease

ABSTRACT Alzheimer disease (AD) is a neurodegenerative disorder for which no approved medication exists. AD is characterized by worsening cognitive and non-cognitive symptoms, and research in the AD field strives to identify very precocious brain alterations leading to an irreversible condition. Recently it has been demonstrated that several early AD symptoms are paralleled with degeneration of neurons producing dopamine (DA), a neurotransmitter involved in the regulation of cognitive and non-cognitive functions. Actually, we found that ventral tegmental area (VTA) DA neurons degenerate early in a validated AD mouse model (Tg2576). Here, we summarize new data showing how macroautophagy/autophagy impairment – due to enhanced activity of the ABL/c-Abl kinase – might cause the DA neuron loss. We also proved that nilotinib, an ABL inhibitor, restores autophagy flux, thus preventing VTA neurodegeneration. Most notably, from a clinical point of view, nilotinib, by preventing DA neuronal loss, preserves DA outflow in VTA-projecting areas, improving Tg2576 behavioral phenotypes. Our findings shed light on the mechanism involved in DA neurodegeneration, revealing that autophagy represents a viable therapeutic target in early AD.

AD "Statin": Alzheimer's Disorder is a "Fast" Disease Preventable by Therapeutic Intervention Initiated Even Late in Life and Reversible at the Early Stages.

The present study posits that Alzheimer's disorder is a "fast" disease. This is in sharp contrast to a view, prevailing until now, that Alzheimer's Disease (AD) is a quintessential "slow" disease that develops throughout the life as one prolonged process. According to this view, beta-amyloid (Aβ) is produced and secreted solely by the beta-amyloid precursor protein (βAPP) proteolytic/secretory pathway. As its extracellular levels increase, it triggers neurodegeneration starting relatively early in life. Damages accumulate and manifest, late in life in sporadic Alzheimer's Disease (SAD) cases, as AD symptoms. In familial AD (FAD) cases, where mutations in βAPP gene or in presenilins increase production of either common Aβ isoform or of its more toxic isoforms, neurodegeneration reaches critical threshold sooner and AD symptoms occur earlier in life, mostly in late 40s and 50s. There are currently no preventive AD therapies but if they were available, according to this viewpoint it would be largely futile to intervene late in life in case of potential SAD or at mid-age in cases of FAD because, although AD symptoms have not yet manifested, the damage has already occurred during the preceding decades. In this paradigm, to be effective, preventive therapeutic intervention should be initiated early in life. The outlook suggested by the present study is radically different. According to it, Alzheimer's disease evolves in two stages. The first stage is a slow process of intracellular beta-amyloid accumulation. It occurs via βAPP proteolytic/secretory pathway and cellular uptake of secreted Aβ common to Homo sapiens, including healthy humans, and to non-human mammals, and results neither in significant damage, nor in manifestation of the disease. The second stage occurs exclusively in humans, commences shortly before symptomatic onset of the disease, sharply accelerates the production and increases intracellular levels of Aβ that is not secreted but is retained intracellularly, generates significant damages, triggers AD symptoms, and is fast. It is driven by an Aβ generation pathway qualitatively and quantitatively different from βAPP proteolytic process and entirely independent of beta-amyloid precursor protein, and results in rapid and substantial intracellular accumulation of Aβ, consequent significant neurodegeneration, and symptomatic AD. In this paradigm, a preventive therapy for AD, an AD "statin", would be effective when initiated at any time prior to commencement of the second stage. Moreover, there are good reasons to believe that with a drug blocking βAPP-independent Aβ production pathway in the second stage, it would be possible not only to preempt the disease but also to stop and to reverse it even when early AD symptoms have already manifested. The present study posits a notion of AD as a Fast Disease, offers evidence for the occurrence of the AD-specific Aβ production pathway, describes cellular and molecular processes constituting an engine that drives Alzheimer's disease, and explains why non-human mammals are not susceptible to AD and why only a subset of humans develop the disease. It establishes that Alzheimer's disease is preventable by therapeutic intervention initiated even late in life, details a powerful mechanism underlying the disease, suggests that Aβ produced in the βAPP-independent pathway is retained intracellularly, elaborates why neither BACE inhibition nor Aβ immunotherapy are effective in treatment of AD and why intracellularly retained beta-amyloid could be the primary agent of neuronal death in Alzheimer's disease, necessitates generation of a novel animal AD model capable of producing Aβ via βAPP-independent pathway, proposes therapeutic targets profoundly different from previously pursued components of the βAPP proteolytic pathway, and provides conceptual rationale for design of drugs that could be used not only preemptively but also for treatment and reversal of the early stages of the disease.

Sources of Response Bias in Cognitive Self-Report Items: "Which Memory Are You Talking About?"

Self-reported cognitive difficulties are common in the years before an Alzheimer's disease (AD) diagnosis. Understanding how older adults interpret and respond to questions about their cognition is critical to recognize response biases that may limit the accuracy of cognitive self-reports in identifying AD risk. Cognitive interviewing is a systematic approach for examining sources of response bias that influence individuals' answers to specific questions. The purpose of this study was to identify features of common cognitive self-report items that contribute to (a) differing interpretations among respondents and (b) older adults' decisional processes when responding. A convenience sample of community-dwelling older adults (n = 49; Mage = 74.5 years; 36.7% male) without dementia completed a demographic questionnaire, the Montreal Cognitive Assessment, and an audio-recorded cognitive interview. Twenty commonly used cognitive self-report items were evaluated using cognitive interviewing techniques. The Question Appraisal System was used to guide the analysis of interview data and identify sources of response bias within and across cognitive self-report items. The most common sources of inconsistency in item interpretation and decisional processes were vague item wording, incorrect assumptions regarding consistency of cognitive problems across situations, and provocation of an emotional reaction that influenced responses. Assessment of self-reported cognition is critical to facilitate research on early AD symptoms. Findings from this study identify modifiable sources of response bias that may influence the measurement properties of currently used cognitive self-report items and can inform refinement of measures.

Tolfenamic Acid Prevents Amyloid β-induced Olfactory Bulb Dysfunction In Vivo.

Amyloid beta inhibits olfactory bulb function. The mechanisms involved in this effect must include alterations in network excitability, inflammation and the activation of different transduction pathways. Thus, here we tested whether tolfenamic acid, a drug that modulates several of these pathological processes, could prevent amyloid beta-induced olfactory bulb dysfunction. To test whether tolfenamic acid prevents amyloid beta-induced alterations in olfactory bulb network function, olfaction and GSK3β activity. The protective effects of tolfenamic acid against amyloid beta-induced population activity inhibition were tested in olfactory bulb slices from adult mice, while tolfenamic acid and amyloid beta were bath-applied. We also tested the effects of amyloid-beta in slices obtained from animals pre-treated chronically (21 days) with tolfenamic acid. The effects of amyloid beta micro-injected into the olfactory bulbs were also tested, after two weeks, on olfactory bulb population activity and olfaction in control and tolfenamic acid chronically treated animals. Olfaction was assessed with the odor-avoidance and the habituation/cross-habituation tests. GSK3β activation was evaluated with Western-blot. Acute bath application of tolfenamic acid does not prevent amyloid beta-induced inhibition of olfactory bulb network activity in vitro. In contrast, chronic treatment with tolfenamic acid renders the olfactory bulb resistant to amyloid beta-induced network activity inhibition in vitro and in vivo, which correlates with the inhibition of GSK3β activation and the protection against amyloid beta-induced olfactory dysfunction. Our data further support the use of tolfenamic acid to prevent amyloid beta-induced pathology and the early symptoms of Alzheimer Disease.

Knowledge on Alzheimer's Disease among Public Hospitals and Health Clinics Pharmacists in the State of Selangor, Malaysia.

The prevalence of Alzheimer's disease (AD) has increased with the fast growing of aging population, thereby posing great challenges to provision of care for AD patients. Pharmacists play a vital role in the management of AD; this includes recognizing early symptoms of AD, providing medication counseling to AD patients and their caretakers, and identifying potential adverse drug reactions. A comprehensive understanding of the disease progression, as well as the pharmacological therapy, is essential to provide effective care to AD patients. The level of knowledge about AD among the pharmacists, however, remains unknown. Hence, this study aimed to assess the knowledge on AD among the pharmacists in public hospitals and health clinics and its correlates. A clear picture of the characteristics associated with different levels of knowledge could facilitate the targeted re-training of pharmacists. The 30-item validated Alzheimer disease knowledge scale (ADKS) tool was pilot-tested and used in this cross-sectional study. All pharmacists, from nine public hospitals and seven public health clinics in the State of Selangor, Malaysia, were invited to participate in this cross-sectional survey. The ADKS score was computed and compared across demographics characteristics. A total of 445 pharmacists responded to the survey. These pharmacists had a moderate overall score in ADKS; nevertheless, high scores were recorded in the domains of treatment management and care giving. No difference in AD knowledge was found among pharmacists worked in public hospitals and health clinics, except for the domain of care giving (p = 0.033). Ethnicity and age group were independent predictors of ADKS score in the current study. The pharmacists in the current study had moderate AD knowledge. On-going education and training programme on AD, in particular the domains other than treatment management and care giving, should be provided to the pharmacists to ensure delivery of quality care to AD patients.

Is sporadic Alzheimer's disease a developmental disorder?

Alzheimer's disease (AD) is a neurodegenerative disorder of higher age that specifically occurs in human. Its clinical phase, characterized by a decline in physiological, psychological, and social functioning, is preceded by a long clinically silent phase of at least several decades that might perhaps even start very early in life. Overall, key functional abilities in AD patients decline in reverse order of the development of these abilities during normal childhood and adolescence. Early symptoms of AD, thus, typically affect mental functions that have been acquired only during very recent hominid evolution and as such are specific to human. Neurofibrillar degeneration, a typical neuropathological lesion of the disease and one of the most robust pathological correlates of cognitive impairment, is rarely seen in non-primate mammals and even non-human primates hardly develop a pathology comparable to those seen in AD patients. Neurofibrillar degeneration is not randomly distributed throughout the AD brain. It preferentially affects brain areas that become increasingly predominant during the evolutionary process of encephalization. During progression of the disease, it affects cortical areas in a stereotypic sequence that inversely recapitulates ontogenetic brain development. The specific distribution of cortical pathology in AD, moreover, appears to be determined by the modular organization of the cerebral cortex which basically is a structural reflection of its ontogeny. Here, we summarize recent evidence that phylogenetic and ontogenetic dimensions of brain structure and function provide the key to our understanding of AD. More recent molecular biological studies of the potential pathogenetic role of a genomic mosaic in the brains of patients with AD might even provide arguments for a developmental origin of AD. This article is part of a series "Beyond Amyloid".

Examination of level of knowledge in Italian general practitioners attending an education session on diagnosis and management of the early stage of Alzheimer's disease: pass or fail?

We detected the general level of knowledge about the early diagnosis of Alzheimer's disease (AD) and subsequent care in general practitioners (GPs) from Southern Italy. We explored also the GP perception about their knowledge and training on diagnosis and management of AD. On a sample of 131 GPs, we administered two questionnaires: the GP-Knowledge, evaluating GPs' expertise about AD epidemiology, differential diagnosis, and available treatments, and the GP-QUestionnaire on Awareness of Dementia (GP-QUAD), assessing the GPs' attitudes, awareness, and practice regarding early diagnosis of dementia. Specific screening tests or protocols to diagnose and manage dementia were not used by 53% of our GPs. The training on the recognition of early AD signs and symptoms was considered inadequate by 55% of the participants. Females were more likely to consider their training insufficient (58%) compared to males (53%). Female GPs were less likely to prescribe antipsychotic drugs to control neuropsychiatric symptoms (NPS) and suggest specialist advice in late stage of cognitive impairment. Multiple Correspondence Analysis (MCA) performed only on GP-QUAD suggested two dimensions explaining 26.1% ("GP attitude") and 20.1% ("GP knowledge") of the inertia for a total of 46.2%, In our survey on GP clinical practice, several problems in properly recognizing early AD symptoms and subsequently screening patients to be referred to secondary/tertiary care centers for diagnosis confirmation have emerged. In the future, specific training programs and educational projects for GPs should be implemented also in Italy to improve detection rates and management of dementia in primary care.

Motivational and cognitive pathways to medical help-seeking for Alzheimer's disease: a cognitive impairment response model.

Relationships among cognitive and motivational factors in predicting medical help-seeking for Alzheimer's disease (AD) symptoms were tested. Community residents awaiting jury service (N = 280) completed questionnaires, including responses to a vignette depicting prototypical early symptoms of AD in a hypothetical mother. Cognitive responses to the vignette included AD symptom identification and AD attribution. Affective-motivational responses to vignettes were symptom impact and behavior appraisals. General knowledge of AD was assessed. Intention to seek medical help was the dependent variable. The impact and identification of AD symptoms, appraisals of risk, and attribution of the scenario to AD were modest, yet all contributed to prediction of medical-help-seeking intentions. The best fitting model had distinct but interrelated cognitive and motivational paths explaining 49% of the variability in medical help-seeking. Motivational variables had particularly important direct and indirect effects on help-seeking. Findings are interpreted as evidence of the importance of motivational as well as cognitive aspects of perceptions of illness behavior in another person. The substantial impact of the tested variables on the desired outcome of medical help-seeking may suggest options for public health efforts to enhance early medical help-seeking for AD that sets the stage for early intervention.

Extracellular chaperones prevent Aβ42-induced toxicity in rat brains

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, formation of the extracellular amyloid β (Aβ42) plaques, neuronal and synapse loss, and activated microglia and astrocytes. Extracellular chaperones, which are known to inhibit amyloid fibril formation and promote clearance of misfolded aggregates, have recently been shown to reduce efficiently the toxicity of HypF-N misfolded oligomers to immortalised cell lines, by binding and clustering them into large species. However, the role of extracellular chaperones on Aβ oligomer toxicity remains unclear, with reports often appearing contradictory. In this study we microinjected into the hippocampus of rat brains Aβ42 oligomers pre-incubated for 1h with two extracellular chaperones, namely clusterin and α2-macroglobulin. The chaperones were found to prevent Aβ42-induced learning and memory impairments, as assessed by the Morris Water Maze test, and reduce Aβ42-induced glia inflammation and neuronal degeneration in rat brains, as probed by fluorescent immunohistochemical analyses. Moreover, the chaperones were able to prevent Aβ42 colocalisation with PSD-95 at post-synaptic terminals of rat primary neurons, suppressing oligomer cytotoxicity. All such effects were not effective by adding pre-formed oligomers and chaperones without preincubation. Molecular chaperones have therefore the potential to prevent the early symptoms of AD, not just by inhibiting Aβ42 aggregation, as previously demonstrated, but also by suppressing the toxicity of Aβ42 oligomers after they are formed. These findings elect them as novel neuroprotectors against amyloid-induced injury and excellent candidates for the design of therapeutic strategies against AD.

Olfactory Dysfunction and Cognitive Impairment in Age-Related Neurodegeneration: Prevalence Related to Patient Selection, Diagnostic Criteria and Therapeutic Treatment of Aged Clients Receiving Clinical Neurology and Community-Based Care

A decrease in olfactory function with age has been attributed to a variety of factors including normal anatomical and physiological changes in aging, surgery, trauma, environmental factors, medications and disease. Olfactory impairment has also been associated with neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease. Deficits in these chemical senses cannot only reduce the pleasure and comfort from food, but represent risk factors for nutritional and immune deficiencies as well as adherence to specific dietary regimens. Therapy is limited, but one should be aware of the existing medical and surgical treatment modalities. Reactive oxygen and nitrogen species, copper and zinc ions, glycating agents and reactive aldehydes, protein cross-linking and proteolytic dysfunction may all contribute to neurodegeneration, olfactory dysfunction, AD. Carnosine (beta-alanyl- L-histidine) is a naturally-occurring, pluripotent, homeostatic transglycating agent. The olfactory lobe is normally enriched in carnosine and zinc. Loss of olfactory function and oxidative damage to olfactory tissue are early symptoms of AD. Protein and lipid oxidation and glycation are integral components of the AD pathophysiology. Carnosine can suppress amyloidbeta peptide toxicity, inhibit production of oxygen free-radicals, scavenge hydroxyl radicals and reactive aldehydes, and suppresses protein glycation. The observations suggest that patented non-hydrolyzed carnosine lubricant drug delivery or perfume toilet water formulations combined with related moiety amino acid structures, such as beta-alanine, should be explored for therapeutic potential towards olfactory dysfunction, AD and other neurodegenerative disorders. "The olfactory system, anatomically, is right in the middle of the part of the brain that's very important for memory. There are strong neural connections between the two." ~ Donald Wilson.

Prolonged Aβ treatment leads to impairment in the ability of primary cortical neurons to maintain K+ and Ca2+ homeostasis

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disease, characterised by the formation of insoluble amyloidogenic plaques and neurofibrillary tangles. Beta amyloid (Aβ) peptide is one of the main constituents in Aβ plaques, and is thought to be a primary causative agent in AD. Neurons are likely to be exposed to chronic, sublethal doses of Aβ over an extended time during the pathogenesis of AD, however most studies published to date using in vitro models have focussed on acute studies. To experimentally model the progressive pathogenesis of AD, we exposed primary cortical neurons daily to 1 μM of Aβ1-40 over 7 days and compared their survival with age-similar untreated cells. We also investigated whether chronic Aβ exposure affects neuronal susceptibility to the subsequent acute excitotoxicity induced by 10 μM glutamate and assessed how Ca2+ and K+ homeostasis were affected by either treatment.ResultsWe show that continuous exposure to 1 μM Aβ1-40 for seven days decreased survival of cultured cortical neurons by 20%. This decrease in survival correlated with increased K+ efflux from the cells. One day treatment with 1 μM Aβ followed by glutamate led to a substantially higher K+ efflux than in the age-similar untreated control. This difference further increased with the duration of the treatment. K+ efflux also remained higher in Aβ treated cells 20 min after glutamate application leading to 2.8-fold higher total K+ effluxed from the cells compared to controls. Ca2+ uptake was significantly higher only after prolonged Aβ treatment with 2.5-fold increase in total Ca2+ uptake over 20 min post glutamate application after six days of Aβ treatment or longer (P < 0.05).ConclusionsOur data suggest that long term exposure to Aβ is detrimental because it reduces the ability of cortical neurons to maintain K+ and Ca2+ homeostasis in response to glutamate challenge, a response that might underlie the early symptoms of AD. The observed inability to maintain K+ homeostasis might furthermore be useful in future studies as an early indicator of pathological changes in response to Aβ.

Calpastatin overexpression attenuates amyloid-β-peptide toxicity in differentiated PC12 cells

Amyloid β peptide (Aβ) plays a major role in the pathogenesis of Alzheimer's disease (AD). Aβ is toxic to neurons, possibly through causing initial synaptic dysfunction and neuronal membrane dystrophy, promoted by increased cellular Ca 2+. Calpain (Ca 2+-dependent protease) and caspase have been implicated in AD. Previously, we used calpain and caspase pharmacological inhibitors to study effects of Aβ25–35 (sAβ) on neuronal-like differentiated PC12 cells. We reported that sAβ-treated cells exhibited calpain activation and protein degradation (due to both calpain and caspase-8). We have now found that overexpression of the calpain specific inhibitor calpastatin in differentiated PC12 cells significantly inhibited the sAβ-induced calpain activation and decreased the protease activity. Calpastatin overexpression inhibited the sAβ-promoted degradation of fodrin, protein kinase Cε, β-catenin (membrane structural proteins and proteins involved in signal transduction pathways), and prevented the sAβ-induced alteration of neurite structure (manifested by varicosities). Overexpression of calpastatin also inhibited Ca 2+-promoted calpain activation and protein degradation; this is consistent with the notion that the Aβ-induced increase in calpain activity results from a rise in cellular Ca 2+, provided the calpastatin level is not so high as to strongly inhibit calpain. Carrying out transfection without selection allowed the comparison in the same culture of calpastatin-overexpressing with non-overexpressing cells. In cultures transfected with green fluorescent protein (GFP)–calpastatin plasmid, calpastatin overexpression (indicated by GFP-labeling) led to inhibition in sAβ-induced membrane propidium iodide (PI) permeability, whereas non-transfected, GFP-unlabeled cells exhibited PI permeability. Overall, the results demonstrate that the effects of Aβ-toxicity studied here were attenuated to a large extent by calpastatin overexpression, indicating that the protease calpain is involved in Aβ-toxicity (obviating a primary, direct role for caspases). Increased expression of calpastatin and/or decrease in calpain may serve as one of the means for ameliorating some of the early symptoms of AD.

Amyloid β peptide toxicity in differentiated PC12 cells: Calpain‐calpastatin, caspase, and membrane damage

Amyloid beta peptide (Abeta) is implicated in the pathogenesis of Alzheimer's disease (AD). The peptide is toxic to neurons, possibly by causing initial synaptic dysfunction and neuronal membrane dystrophy, promoted by increased cellular Ca(2+). Calpain (Ca(2+)-dependent protease) and caspase have also been implicated in AD. There is little information on communication between the two proteases or on the involvement of calpastatin (the specific calpain inhibitor) in Abeta toxicity. We studied the effects of Abeta25-35 (sAbeta) on calpain, calpastatin, and caspase in neuronal-like differentiated PC12 cells. sAbeta-treated cells exhibited primarily cell membrane damage (varicosities along neurites, enhanced membrane permeability to propidium iodide, without apparent nuclear changes of apoptosis, and little poly (ADP-ribose) polymerase [PARP] degradation). The sAbeta-induced membrane damage is in contrast with staurosporine-induced damage (nuclear apoptotic changes, PARP degradation, without membrane propidium iodide permeability). sAbeta led to activation of caspase-8 and calpain, promotion of calpastatin degradation (by caspase-8 and by calpain), and enhanced degradation of fodrin (mainly by calpain). The results support the idea that Abeta causes primarily neuronal membrane dysfunction, and point to cross-talk between calpain and caspase (protease activation and degradation of calpastatin) in Abeta toxicity. Increased expression of calpastatin and/or decrease in calpain and caspase-8 may serve as means for ameliorating early symptoms of AD.

Cost-effective recognition and diagnosis of dementia.

Alzheimer's disease (AD) has the potential to become the most overwhelming public health concern of this century due to increasing life expectancy and growth in the aging population. As a result, primary care physicians and neurologists will be seeing a greater number of elderly patients in their practice and will subsequently be expected to both identify and initiate treatment in those individuals who may display signs of dementia and related neurologic conditions. There is good evidence that AD is underrecognized or undercoded in primary care settings. Underrecognition is an important problem in this population because early treatment and counseling have been shown to provide benefits to both patients and caregivers. As their patient population ages, physicians need to learn to recognize the early symptoms of AD and make a diagnosis in order to provide cost-effective therapies.