Event In Alzheimer's Disease Research Articles

Atomic Structures of Amyloid-β Oligomers Illuminate a Neurotoxic Mechanism

Amyloid-β (Aβ) accumulation in the brain is a cardinal event in Alzheimer's disease (AD), but the structural basis of Aβ-elicited neurotoxicity is unknown. In a recent paper, Ciudad et al. elucidate the first atomic structures of Aβ oligomers, which reveal how they form lipid-stabilized pores that might disrupt neuronal membranes and ion homeostasis.

Self-defining Memories and their Contribution to the Sense of Self in Alzheimer's Disease.

Unlike autobiographical memory (i.e., memory for personal information) in Alzheimer's Disease (AD), little is known about Self-Defining Memories (SDM) (i.e., memories of highly significant personal events) in AD. The characteristics of self-defining memories in AD were evaluated by analyzing their specificity, emotional valence, and integration, as well as their centrality and contribution to self-continuity. Results demonstrated fewer specific SDM in AD participants than in controls. No significant differences were observed between AD participants and controls regarding the production of positive or integrated SDM. Furthermore, no significant differences were observed between AD participants and controls regarding the rating of the centrality of SDM and their contribution to self-continuity. These results demonstrate that, although AD participants produce fewer specific SDM than controls, both populations have similar levels of emotional valence, integration, centrality, and selfcontinuity of these memories. It is concluded that patients with AD, at least those in the mild stages of the disease, can build on significant personal events and experiences (i.e., SDM) to reflect on how these events have changed the way they see themselves.

ALDH2 contributes to melatonin-induced protection against APP/PS1 mutation-prompted cardiac anomalies through cGAS-STING-TBK1-mediated regulation of mitophagy

Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease (AD), although neither precise etiology nor effective treatment is available. This study was designed to evaluate cardiac function in AD patients and APP/PS1 mutant mice, along with circulating levels of melatonin, mitochondrial aldehyde dehydrogenase (ALDH2) and autophagy. AD patients and APP/PS1 mice displayed cognitive and myocardial deficits, low levels of circulating melatonin, ALDH2 activity, and autophagy, ultrastructural, geometric (cardiac atrophy and interstitial fibrosis) and functional (reduced fractional shortening and cardiomyocyte contraction) anomalies, mitochondrial injury, cytosolic mtDNA buildup, apoptosis, and suppressed autophagy and mitophagy. APP/PS1 mutation downregulated cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) levels and TBK1 phosphorylation, while promoting Aβ accumulation. Treatment with melatonin overtly ameliorated unfavorable APP/PS1-induced changes in cardiac geometry and function, apoptosis, mitochondrial integrity, cytosolic mtDNA accumulation (using both immunocytochemistry and qPCR), mitophagy, and cGAS-STING-TBK1 signaling, although these benefits were absent in APP/PS1/ALDH2−/− mice. In vitro evidence indicated that melatonin attenuated APP/PS1-induced suppression of mitophagy and cardiomyocyte function, and the effect was negated by the nonselective melatonin receptor blocker luzindole, inhibitors or RNA interference of cGAS, STING, TBK1, and autophagy. Our data collectively established a correlation among cardiac dysfunction, low levels of melatonin, ALDH2 activity, and autophagy in AD patients, with compelling support in APP/PS1 mice, in which melatonin rescued myopathic changes by promoting cGAS-STING-TBK1 signaling and mitophagy via an ALDH2-dependent mechanism.

Longitudinal Cognitive and Biomarker Measurements Support a Unidirectional Pathway in Alzheimer’s Disease Pathophysiology

BackgroundAmyloid-β (Aβ) likely plays a primary role in Alzheimer’s disease pathogenesis, but longitudinal Aβ, tau, and neurodegeneration (A/T/N) measurements in the same individuals have rarely been examined to verify the temporal dynamics of these biomarkers. MethodsIn this study, we investigated the temporal ordering of Aβ, tau, and neurodegeneration using longitudinal biomarkers in nondemented elderly individuals. A total of 395 cognitively unimpaired individuals and 204 individuals with mild cognitive impairment (320 [53%] were female) were classified into 8 A±/T±/N± categories according to the abnormal (+)/normal (–) status of Aβ (18F-florbetapir or 18F-florbetaben) positron emission tomography (PET), 18F-flortaucipir PET, and adjusted hippocampal volume (aHCV). Follow-up Aβ PET, tau PET, and aHCV measurements at 0.6 to 4.1 years were available for 35% to 63% of the sample. Baseline Aβ, tau, and aHCV were compared between different A/T/N profiles. We investigated the associations of baseline and longitudinal Aβ, tau, and neurodegeneration in relation to one another continuously. ResultsAmong T– participants, tau was higher for A+/T–/N– individuals compared with the A–/T–/N– group (p = .02). Among N– participants, neurodegeneration was worse among A+/T+/N– individuals compared with the A–/T–/N– group (p = .001). High baseline Aβ was associated (p < .001) with subsequent tau increase and high baseline tau was associated (p = .002) with subsequent aHCV decrease, whereas high tau and low aHCV at baseline were not associated with subsequent Aβ increase. ConclusionsThese findings define a sequence of pathological events in Alzheimer’s disease that support a current model of Alzheimer’s disease pathogenesis in which Aβ appears early, followed by deposition of abnormal tau aggregates and subsequent neurodegeneration.

Robust light\u2013dark patterns and reduced amyloid load in an Alzheimer\u2019s disease transgenic mouse model

Circadian disruption resulting from exposure to irregular light–dark patterns and sleep deprivation has been associated with beta amyloid peptide (Aβ) aggregation, which is a major event in Alzheimer’s disease (AD) pathology. We exposed 5XFAD mice and littermate controls to dim-light vs. bright-light photophases to investigate the effects of altering photophase strength on AD-associated differences in cortical Aβ42 levels, wheel-running activity, and circadian free-running period (tauDD). We found that increasing light levels significantly reduced cortical Aβ42 accumulation and activity levels during the light phase of the light:dark cycle, the latter being consistent with decreased sleep fragmentation and increased sleep duration for mice exposed to the more robust light–dark pattern. No significant changes were observed for tauDD. Our results are consistent with circadian pacemaker period being relatively unaffected by Aβ pathology in AD, and with reductions in cortical Aβ loads in AD through tailored lighting interventions.

Expression levels of the α7 nicotinic acetylcholine receptor in the brains of patients with Alzheimer's disease and their effect on synaptic proteins in SH-SY5Y cells.

Alzheimer's disease (AD) is a chronic neurodegenerative, and abnormal aggregation of the neurotoxic β amyloid (Aβ) peptide is an early event in AD. The present study aimed to determine the correlation between the nicotinic acetylcholine receptor α7 subunit (α7 nAChR) and Aβ in the brains of patients with AD, and to investigate whether the increased expression levels of the α7 nAChR could alter the neurotoxicity of Aβ. The expression levels of α7 nAChR and Aβ in the brains of patients with AD and healthy brains were analyzed using immunofluorescence. Moreover, SH-SY5Y cells were used to stably overexpress or silence α7 nAChR expression levels, prior to the treatment with or without 1 µmol/l Aβ1-42 oligomer (AβO). The mRNA and protein expression levels of α7 nAChR, synaptophysin (SYP), postsynaptic density of 95 kDa (PSD-95) and synaptosomal-associated protein of 25 kDa (SNAP-25) were subsequently analyzed using reverse transcription-quantitative PCR and western blotting. In addition, the concentration of acetylcholine (ACh) and the activity of acetylcholinesterase (AChE) were analyzed using spectrophotometry, while the cell apoptotic rate was determined using flow cytometry. The expression of Aβ in the brains of patients with AD was found to be significantly increased, whereas the expression of α7 nAChR was significantly decreased compared with the healthy control group. In vitro, the expression levels of α7 nAChR were significantly increased or decreased following the overexpression or silencing of the gene, respectively. Consistent with these observations, the mRNA and protein expression levels of SYP, PSD-95 and SNAP-25 were also significantly increased following the overexpression of α7 nAChR and decreased following the genetic silencing of the receptor. In untransfected or negative control cells, the expression levels of these factors and the apoptotic rate were significantly reduced following the exposure to AβO, which was found to be attenuated by α7 nAChR overexpression, but potentiated by α7 nAChR RNA silencing. However, no significant differences were observed in either the ACh concentration or AChE activity following transfection. Collectively, these findings suggested that α7 nAChR may protect the brains of patients with AD against Aβ, as α7 nAChR overexpression increased the expression levels of SYP, SNAP-25 and PSD-95, and attenuated the inhibitory effect of Aβ on the expression of these synaptic proteins and cell apoptosis. Overall, this indicated that α7 nAChR may serve an important neuroprotective role in AD.

APOE \u03b54 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer\u2019s disease

BackgroundAggregation of amyloid β into plaques in the brain is one of the earliest pathological events in Alzheimer’s disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) ε4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid β aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE ε4 genotype.MethodsWe tested 243 proteins and protein fragments in CSF comparing 193 subjects with AD across the cognitive spectrum (65% APOE ε4 carriers, average age 75 ± 7 years) against 60 controls with normal CSF amyloid β, normal cognition, and no APOE ε4 allele (average age 75 ± 6 years).ResultsOne hundred twenty-nine proteins (53%) were associated with aggregated amyloid β. APOE ε4 carriers with AD showed altered concentrations of proteins involved in the complement pathway and glycolysis when cognition was normal and lower concentrations of proteins involved in synapse structure and function when cognitive impairment was moderately severe. APOE ε4 non-carriers with AD showed lower expression of proteins involved in synapse structure and function when cognition was normal and lower concentrations of proteins that were associated with complement and other inflammatory processes when cognitive impairment was mild. Repeating analyses for 114 proteins that were available in an independent EMIF-AD MBD dataset (n = 275) showed that 80% of the proteins showed group differences in a similar direction, but overall, 28% effects reached statistical significance (ranging between 6 and 87% depending on the disease stage and genotype), suggesting variable reproducibility.ConclusionsThese results imply that AD pathophysiology depends on APOE genotype and that treatment for AD may need to be tailored according to APOE genotype and severity of the cognitive impairment.

Prodromal Intestinal Events in Alzheimer's Disease (AD): Colonic Dysmotility and Inflammation Are Associated with Enteric AD-Related Protein Deposition.

Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer’s disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age. In vitro colonic motility was examined. Faecal and colonic Aβ, tau proteins, α-synuclein and IL-1β were assessed by ELISA. Colonic citrate synthase activity was assessed by spectrophotometry. Colonic NLRP3, caspase-1 and ASC expression were evaluated by Western blotting. Colonic eosinophil density and claudin-1 expression were evaluated by immunohistochemistry. The effect of Aβ on NLRP3 signalling and mitochondrial function was tested in cultured cells. Cognitive impairment and decreased faecal output occurred in SAMP8 mice from six months. When compared with SAMR1, SAMP8 animals displayed: (1) impaired in vitro colonic contractions; (2) increased enteric AD-related proteins, IL-1β, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, Aβ promoted IL-1β release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC-/- cells. Aβ decreased mitochondrial function in THP-1 cells. In SAMP8, enteric AD-related proteins deposition, inflammation and impaired colonic excitatory neurotransmission, occurring before the full brain pathology development, could contribute to bowel dysmotility and represent prodromal events in AD.

PNU282987 inhibits amyloid‑β aggregation by upregulating astrocytic endogenous αB‑crystallin and HSP‑70 via regulation of the α7AChR, PI3K/Akt/HSF‑1 signaling axis.

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disorder. Abnormal aggregation of the neurotoxic amyloid-β (Aβ) peptide is an early event in AD. The activation of astrocytic α7 nicotinic acetylcholine receptor (α7 nAChR) can inhibit Aβ aggregation; thus, the molecular mechanism between α7 nAChR activation and Aβ aggregation warrants further investigation. In the present study, Aβ oligomer levels were assessed in astrocytic cell lysates after treatment with PNU282987 (a potent agonist of α7 nAChRs) or co-treatment with LY294002, a p-Akt inhibitor. The levels of heat shock factor-1 (HSF-1), heat shock protein 70 (HSP-70), and αB-crystallin (Cryab) in astrocytes treated with PNU282987 at various time-points or co-treated with methyllycaconitine (MLA), a selective α7 nAChR antagonist, as well as co-incubated with LY294002 were determined by western blotting. HSP-70 and Cryab levels were determined after HSF-1 knockdown (KD) in astrocytes. PNU282987 markedly inhibited Aβ aggregation and upregulated HSF-1, Cryab, and HSP-70 in primary astrocytes, while the PNU282987-mediated neuroprotective effect was reversed by pre-treatment with MLA or LY294002. Moreover, the HSF-1 KD in astrocytes effectively decreased Cryab, but not HSP-70 expression. HSF-1 is necessary for the upregulation of Cryab expression, but not for that of HSP-70. HSF-1 and HSP-70 have a neuroprotective effect. Furthermore, the neuroprotective effect of PNU282987 against Aβ aggregation was mediated by the canonical PI3K/Akt signaling pathway activation.

Nasal delivery of a CRMP2-derived CBD3 adenovirus improves cognitive function and pathology in APP/PS1 transgenic mice

Calcium dysregulation is a key pathological event in Alzheimer’s disease (AD). In studying approaches to mitigate this calcium overload, we identified the collapsin response mediator protein 2 (CRMP2), an axonal guidance protein that participates in synapse dynamics by interacting with and regulating activity of N-methyl-D-aspartate receptors (NMDARs). We further identified a 15 amino acid peptide from CRMP2 (designated CBD3, for calcium-binding domain 3), that reduced NMDAR-mediated Ca2+ influx in cultured neurons and post-synaptic NMDAR-mediated currents in cortical slices. Whether targeting CRMP2 could be therapeutically beneficial in AD is unknown. Here, using CBD3, we tested the utility of this approach. Employing the APP/PS1 mouse model of AD which demonstrates robust pathophysiology including Aβ1–42 deposition, altered tau levels, and diminished cognitive functions, we asked if overexpression of CBD3 could rescue these events. CBD3 was engineered into an adeno-associated vector and nasally delivered into APP/PS1 mice and then biochemical (immunohistochemistry, immunoblotting), cellular (TUNEL apoptosis assays), and behavioral (Morris water maze test) assessments were performed. APP/PS1 mice administered adeno-associated virus (AAV, serotype 2) harboring CBD3 demonstrated: (i) reduced levels of Aβ1–42 and phosphorylated-tau (a marker of AD progression), (ii) reduced apoptosis in the hippocampus, and (iii) reduced cognitive decline compared with APP/PS1 mice or APP/PS1 administered a control virus. These results provide an instructive example of utilizing a peptide-based approach to unravel protein-protein interactions that are necessary for AD pathology and demonstrate the therapeutic potential of CRMP2 as a novel protein player in AD.

Social networks in mild-to-moderate Alzheimer disease: longitudinal relationships with dementia severity, cognitive function, and adverse events

Objectives Poor social networks are associated with a greater likelihood of cognitive decline, dementia, and other adverse health outcomes in later life. However, these relationships have been poorly explored in those with established Alzheimer Disease (AD), who may represent a particularly vulnerable group. Methods Analysis of data from the NILVAD study. We assessed social networks (Lubben Social Network Scale [LSNS]), cognition (Alzheimer’s disease Assessment Scale [ADAS-Cog]) and dementia severity (Clinical Dementia Rating, Sum of Boxes [CDR-Sb]) in older adults with mild-moderate AD at baseline and at 18 months. Results 464 participants with mild-to-moderate AD were included (73.1 ± 8.3 years; 61.9% female). At baseline, a poor social network was significantly associated with a greater dementia severity, but not greater cognitive impairment. Rather than a poor social network predicting greater cognitive decline over 18 months, a greater baseline dementia severity predicted a decline in social network over 18 months (β: −0.22, −0.42 – −0.02, p = 0.034). Finally, a poor social network was associated with a significantly increased likelihood of experiencing serious adverse events (IRR: 1.41, 1.06–1.89, p = 0.019). Discussion As dementia progresses, older adults with AD are more likely to experience a decline in social network. Further, having a poor social network was associated with a greater likelihood of experiencing serious adverse events. These findings add novel insight into the complex relationship between social networks, dementia progression and adverse events in AD, and underscore the importance of developing and maintaining social networks in AD.

Prevalence of and risk factors for adverse events in Alzheimer's patients receiving anti-dementia drugs in at-home care.

The objective of this study was to clarify the types and prevalence of, and the risk factors for, the adverse events that occur in patients receiving anti-dementia drugs. A questionnaire survey was conducted. The respondents were pharmacists who were dispensing anti-dementia drugs. The pharmacists responded to questions about patients who were receiving anti-dementia drugs delivered to them at home by the pharmacists. The survey questions included questions about whether or not the patients experienced adverse reactions to the drugs, about the patients' background characteristics, about the numbers of drugs the patients were taking when the pharmacists first visited the patients at home, and about the pharmacists' assessments of the appropriateness of the use of the anti-dementia drugs. Data were collected on 3712 patients from 1673 pharmacies in a nationwide survey. Anti-dementia drugs had been prescribed to 863 of these patients; and 801 (92.8%) of these 863 patients were 75 years of age or older, and. confirmed adverse events occurred in 170 (21%) of these 863 patients. The most common adverse event was excitation/anxiety, at 45.1%. A multivariate analysis found that polypharmacy (10 or more types of drugs per day) (P = 0.030), inappropriate use (P = 0.002), and irregular medication use (P = 0.034) were risk factors. In order to avoid adverse events when using anti-dementia drugs, doctors and pharmacists should carefully examine the prescribing of multiple medications, assess the applicability of the use of anti-dementia drugs, and investigate how to best manage patients' drug use.

Acute Pannexin 1 Blockade Mitigates Early Synaptic Plasticity Defects in a Mouse Model of Alzheimer's Disease.

Synaptic loss induced by soluble oligomeric forms of the amyloid β peptide (sAβos) is one of the earliest events in Alzheimer’s disease (AD) and is thought to be the major cause of the cognitive deficits. These abnormalities rely on defects in synaptic plasticity, a series of events manifested as activity-dependent modifications in synaptic structure and function. It has been reported that pannexin 1 (Panx1), a nonselective channel implicated in cell communication and intracellular signaling, modulates the induction of excitatory synaptic plasticity under physiological contexts and contributes to neuronal death under inflammatory conditions. Here, we decided to study the involvement of Panx1 in functional and structural defects observed in excitatory synapses of the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mice, an animal model of AD. We found an age-dependent increase in the Panx1 expression that correlates with increased Aβ levels in hippocampal tissue from Tg mice. Congruently, we also observed an exacerbated Panx1 activity upon basal conditions and in response to glutamate receptor activation. The acute inhibition of Panx1 activity with the drug probenecid (PBN) did not change neurodegenerative parameters such as amyloid deposition or astrogliosis, but it significantly reduced excitatory synaptic defects in the AD model by normalizing long-term potentiation (LTP) and depression and improving dendritic arborization and spine density in hippocampal neurons of the Tg mice. These results suggest a major contribution of Panx1 in the early mechanisms leading to the synaptopathy in AD. Indeed, PBN induced a reduction in the activation of p38 mitogen-activated protein kinase (MAPK), a kinase widely implicated in the early neurotoxic signaling in AD. Our data strongly suggest that an enhanced expression and activation of Panx1 channels contribute to the Aβ-induced cascades leading to synaptic dysfunction in AD.

Cysteine string proteins.

Cysteine string protein (CSP) was discovered by use of a synapse-specific, monoclonal antibody to screen a cDNA expression library in Drosophila. A vertebrate CSP homolog was later identified and shown to co-purify with synaptic vesicles. CSP-α is now recognized as a membrane constituent of many regulated secretory organelles. Knockout of the csp gene in Drosophila produced temperature-sensitive paralysis reflecting a loss of evoked (but not spontaneous) transmitter release. However, CSP's role in regulated exocytosis remains ambiguous. Fruit flies lacking the csp gene also exhibited nerve terminal degeneration as did mice deficient in the csp-α gene. This phenotype has been ascribed to the depletion of a functional pool of the t-SNARE, SNAP-25. However, recent studies showing that an endosomal pool of CSP-α contributes to a novel, protein-export pathway argues that CSP's role in neurodegeneration is more complex. Clients of this later pathway include tau and α-synuclein, proteins linked to neurodegeneration. Additionally, mutations in the csp-α gene cause an adult-onset, neuronal ceroid lipofuscinosis and diminished CSP-α expression is an early event in Alzheimer's disease. Collectively, these findings indicate that much remains to be learned about the role of CSPs in cellular secretory pathways and human disease.

Femtomolar sensing of Alzheimer's tau proteins by water oxidation-coupled photoelectrochemical platform

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. A key pathogenic event of AD is the formation of intracellular neurofibrillary tangles that are mainly composed of tau proteins. Here, we report on ultrasensitive detection of total tau (t-tau) proteins using an artificial electron donor-free, BiVO4-based photoelectrochemical (PEC) analysis. The platform was constructed by incorporating molybdenum (Mo) dopant and iron oxyhydroxide (FeOOH) ad-layer into the BiVO4 photoelectrode and employing a signal amplifier formed by horseradish peroxidase (HRP)-triggered oxidation of 3,3′-diaminobenzidine (DAB). Despite the absence of additional electron suppliers, the FeOOH/Mo:BiVO4 conjugated with the Tau5 antibody produced strong current signals at 0 V (vs. Ag/AgCl, 3 M NaCl) under the illumination of a white light-emitting diode. The Mo extrinsic dopants increased the charge carrier density of BiVO4-Tau5 by 1.57 times, and the FeOOH co-catalyst promoted the interfacial water oxidation reaction of Mo:BiVO4-Tau5 by suppressing charge recombination. The introduction of HRP-labeled Tau46 capture antibodies to the FeOOH/Mo:BiVO4-Tau5 platform produced insoluble precipitation on the transducer by accelerating the oxidation of DAB, which amplified the photocurrent signal of FeOOH/Mo:BiVO4-Tau5 by 2.07-fold. Consequently, the water oxidation-coupled, FeOOH/Mo:BiVO4-based PEC sensing platform accurately and selectively recognized t-tau proteins down to femtomolar concentrations; the limit of detection and limit of quantification were determined to be 1.59 fM and 4.11 fM, respectively.

Autophagy modulates Aβ accumulation and formation of aggregates in yeast

Intracellular accumulation of amyloid-β protein (Aβ) is an early event in Alzheimer's disease (AD). The autophagy-lysosomal pathway is an important pathway for maintaining cellular proteostasis and for the removal of damaged organelles and protein aggregates in all eukaryotes. Despite mounting evidence showing that modulating autophagy promotes clearance of Aβ aggregates, the regulatory mechanisms and signalling pathways underlying this process remain poorly understood. In order to gain better insight we used our previously characterised yeast model expressing GFP-Aβ42 to identify genes that regulate the removal of Aβ42 aggregates by autophagy. We report that GFP-Aβ42 is sequestered and is selectively transported to vacuole for degradation and that autophagy is the prominent pathway for clearance of aggregates. Next, to identify genes that selectively promote the removal of Aβ42 aggregates, we screened levels of GFP-Aβ42 and non-aggregating GFP-Aβ42 (19:34) proteins in a panel of 192 autophagy mutants lacking genes involved in regulation and initiation of the pathway, cargo selection and degradation processes. The nutrient and stress signalling genes RRD1, SNF4, GCN4 and SSE1 were identified. Deletion of these genes impaired GFP-Aβ42 clearance and their overexpression reduced GFP-Aβ42 levels in yeast. Overall, our findings identify a novel role for these nutrient and stress signalling genes in the targeted elimination of Aβ42 aggregates, which offer a promising avenue for developing autophagy based therapies to suppress amyloid deposition in AD.

Complement-Mediated Events in Alzheimer's Disease: Mechanisms and Potential Therapeutic Targets.

An estimated 5.7 million Americans suffer from Alzheimer's disease in the United States, with no disease-modifying treatments to prevent or treat cognitive deficits associated with the disease. Genome-wide association studies suggest that an enhancement of clearance mechanisms and/or promotion of an anti-inflammatory response may slow or prevent disease progression. Increasing awareness of distinct roles of complement components in normal brain development and function and in neurodegenerative disorders align with complement-mediated responses, and thus, thorough understanding of these molecular pathways is needed to facilitate successful therapeutic design. Both beneficial and detrimental effects of C1q as well as contributions to local inflammation by C5a-C5aR1 signaling in brain highlight the need for precision of therapeutic design. The potential benefit of β-amyloid clearance from the circulation via CR1-mediated mechanisms is also reviewed. Therapies that suppress inflammation while preserving protective effects of complement could be tested now to slow the progression of this debilitating disease.

Amyloidogenic Nanoplaques in Cerebrospinal Fluid: Relationship to Amyloid Brain Uptake and Clinical Alzheimer’s Disease in a Memory Clinic Cohort

Background:Aggregation of amyloid-β (Aβ) is an early pathological event in Alzheimer’s disease (AD). Consequently, measures of pathogenic aggregated Aβ are attractive biomarkers for AD. Here, we use a recently developed Thioflavin-T-Fluorescence Correlation Spectroscopy (ThT-FCS) assay to quantify structured ThT-responsive protein aggregates, so-called nanoplaques, in the cerebrospinal fluid (CSF).Objective:The overall aim of this work was to assess whether ThT-FCS determined CSF nanoplaque levels could predict amyloid brain uptake as determined by 18F-Flutemetamol PET analysis. Further, we assess whether nanoplaque levels could predict clinical AD.Methods:Nanoplaque levels in the CSF from 54 memory clinic patients were compared between sub-groups classified by 18F-Flutemetamol PET as amyloid-positive or amyloid-negative, and by clinical assessment as AD or non-AD.Results:Nanoplaque levels did not differ between amyloid groups and could not predict brain amyloid uptake. However, nanoplaque levels were significantly increased in patients with clinical AD, and were significant predictors for AD when adjusting for age, sex, cognitive function, and apolipoprotein E (APOE) genotype.Conclusion:The concentration of nanoplaques in the CSF differentiates patients with clinical AD from non-AD patients.

Kinesin light chain-1 serine-460 phosphorylation is altered in Alzheimer\u2019s disease and regulates axonal transport and processing of the amyloid precursor protein

Damage to axonal transport is an early pathogenic event in Alzheimer’s disease. The amyloid precursor protein (APP) is a key axonal transport cargo since disruption to APP transport promotes amyloidogenic processing of APP. Moreover, altered APP processing itself disrupts axonal transport. The mechanisms that regulate axonal transport of APP are therefore directly relevant to Alzheimer’s disease pathogenesis. APP is transported anterogradely through axons on kinesin-1 motors and one route for this transport involves calsyntenin-1, a type-1 membrane spanning protein that acts as a direct ligand for kinesin-1 light chains (KLCs). Thus, loss of calsyntenin-1 disrupts APP axonal transport and promotes amyloidogenic processing of APP. Phosphorylation of KLC1 on serine-460 has been shown to reduce anterograde axonal transport of calsyntenin-1 by inhibiting the KLC1-calsyntenin-1 interaction. Here we demonstrate that in Alzheimer’s disease frontal cortex, KLC1 levels are reduced and the relative levels of KLC1 serine-460 phosphorylation are increased; these changes occur relatively early in the disease process. We also show that a KLC1 serine-460 phosphomimetic mutant inhibits axonal transport of APP in both mammalian neurons in culture and in Drosophila neurons in vivo. Finally, we demonstrate that expression of the KLC1 serine-460 phosphomimetic mutant promotes amyloidogenic processing of APP. Together, these results suggest that increased KLC1 serine-460 phosphorylation contributes to Alzheimer’s disease.

Neuroprotective effect of CPCGI on Alzheimer's disease and its mechanism.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder causing progressive memory loss and cognitive impairment. The aberrant accumulation of amyloid-β (Aβ) and neuroinflammation are two major events in AD. Aβ-induced neurotoxicity and oxidative stress are also involved in the pathogenesis of AD. The purpose of the current study was to investigate the effect of compound porcine cerebroside and ganglioside injection (CPCGI) on the progression of AD, and to explore the molecular mechanism. In vivo and in vitro models of AD were established and treated with CPCGI. Aβ40 and Aβ42 protein levels were detected using western blotting. Production of pro-inflammatory factors [tumor necrosis factor (TNF)-α and interleukin (IL)-1β] and oxidative stress markers [malondialdehyde (MDA), superoxide dismutase (SOD)] and reactive oxygen species (ROS) production were determined. Cell viability and apoptosis were detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5- diphenyl-2-H-tetrazolium bromide assay and flow cytometry analysis respectively. Results demonstrated that CPCGI administration reduced Aβ40 and Aβ42 accumulation, and inhibited inflammatory response and oxidative stress in the in vivo rat model of AD, evidenced by decreased Aβ40 and Aβ42 protein expression, reduced levels of TNF-α and IL-1β, reduced MDA content, enhanced SOD activity, and reduced ROS level. It was found that CPCGI enhanced cell viability and reduced cell apoptosis of Aβ25-35 induced PC12 cells. In addition, the mitogen-activated protein kinase/NF-κB pathway was involved in the protective effect of CPCGI on AD. Taken together, the data demonstrated that CPCGI exerted a protective effect on AD by reducing Aβ accumulation, inhibiting inflammatory response and oxidative stress, In addition to preventing neuronal apoptosis.