Elevated Beta-amyloid Research Articles

Differential risk of Alzheimer's disease in MCI subjects with elevated Abeta

BackgroundsPeople with elevated beta amyloid have different risk and progress speed to Alzheimer's disease. PurposeThe research is to validate the risk classification of AD developed in the Shanghai mild cognitive impairment (MCI) cohort study using ADNI data. MethodsThe risk classification of AD in MCI was based on several optimal cut-off points of a novel parameter Cog_Vol. ResultsIn total, 843 subjects with MCI were included, of whom 220 had elevated PET beta amyloid. 273 (32.3 %) and 70 (31.8 %) progressed to AD in all subjects and in those with elevated PET beta amyloid, respectively. The risk of AD in subjects whose Cog_Vol >340 was very low, while the risk for those with Cog_Vol less than 101 indicated a super high within 4 years of follow-up. DiscussionRisk classification using Cog_Vol at an optimal value was able to detect subjects among those with PET-amyloid-elevated MCI were at greater risk of developing AD and were unlikely to develop AD within 4 years of follow-up.

Amyloid beta-induced mitochondrial dysfunction and endothelial permeability in cerebral microvascular endothelial cells: The protective role of dexmedetomidine

Postoperative cognitive dysfunction (POCD) is a common complication in patients who undergo anesthesia in different types of surgeries. Emerging evidence implicates elevated beta-amyloid (Aβ) in the pathogenesis of POCD. Meanwhile, Dexmedetomidine (DEX) has recently shown promise in reducing POCD incidence. This study aimed to elucidate the role of Aβ in inducing endothelial permeability in cerebral microvascular endothelial cells and the underlying mechanisms and testing the effects of DEX. We demonstrated that Aβ1–42, the prevalent Aβ form related to POCD, is cytotoxic to HBMECs, increasing transendothelial permeability and inducing mitochondrial dysfunction, as evidenced by elevated mitochondrial reactive oxygen species (ROS) and decreased ATP production and mitochondrial membrane potential. Furthermore, Aβ1–42 was shown to inhibit Sirt3, exacerbating mitochondrial dysfunction. Conversely, DEX was found to prevent Aβ1–42-induced mitochondrial dysfunction and permeability increases and preserved tight junction proteins in HBMECs.These findings suggest that DEX, as a Sirt3 activator, may offer a pharmacological strategy to mitigate Aβ1–42-related cerebral microvascular endothelial cell dysfunction and preserve cognitive function post-surgery.

Association of Novelty-Related Locus Coeruleus Function With Entorhinal Tau Deposition and Memory Decline in Preclinical Alzheimer Disease.

The predictable Braak staging scheme suggests that cortical tau progression may be related to synaptically connected neurons. Animal and human neuroimaging studies demonstrated that changes in neuronal activity contribute to tau spreading. Whether similar mechanisms explain tau progression from the locus coeruleus (LC), a tiny noradrenergic brainstem nucleus involved in novelty, learning, and memory and among the earliest regions to accumulate tau, has not yet been established. We aimed to investigate whether novelty-related LC activity was associated with the accumulation of cortical tau and its implications for cognitive decline. We combined functional MRI data of a novel vs repeated face-name learning paradigm, [18F]-FTP-PET, [11C]-PiB-PET, and longitudinal cognitive data from 92 well-characterized older individuals in the Harvard Aging Brain Study. We related novelty vs repetition LC activity to cortical tau deposition and to longitudinal decline in memory, executive function, and the Preclinical Alzheimer Disease Cognitive Composite (version 5; PACC5). Structural equation modeling was used to examine whether entorhinal cortical (EC) tau mediated the relationship between LC activity and cognitive decline and whether this depended on beta-amyloid deposition. The participants' average age at baseline was 69.67 ± 10.14 years. Fifty-one participants were female. Ninety-one participants were cognitively normal (CDR global = 0), and one participant had mild cognitive impairment (CDR global = 0.5) at baseline. Lower novelty-related LC activity was specifically related to greater tau deposition in the medial-lateral temporal cortex and steeper memory decline. LC activity during novelty vs repetition was not related to executive dysfunction or decline on the PACC5. The relationship between LC activity and memory decline was partially mediated by EC tau, particularly in individuals with elevated beta-amyloid deposition. Our results suggested that lower novelty-related LC activity is associated with the emergence of EC tau and that the downstream effects of this LC-EC pathway on memory decline also require the presence of elevated beta-amyloid. Longitudinal studies are required to investigate whether optimal LC activity has the potential to delay tau spread and memory decline, which may have implications for designing targeted interventions promoting resilience.

Severe CTE and TDP-43 pathology in a former professional soccer player with dementia: a clinicopathological case report and review of the literature

In the last decades, numerous post-mortem case series have documented chronic traumatic encephalopathy (CTE) in former contact-sport athletes, though reports of CTE pathology in former soccer players are scarce. This study presents a clinicopathological case of a former professional soccer player with young-onset dementia. The patient experienced early onset progressive cognitive decline and developed dementia in his mid-50 s, after playing soccer for 12 years at a professional level. While the clinical picture mimicked Alzheimer’s disease, amyloid PET imaging did not provide evidence of elevated beta-amyloid plaque density. After he died in his mid-60 s, brain autopsy showed severe phosphorylated tau (p-tau) abnormalities fulfilling the neuropathological criteria for high-stage CTE, as well as astrocytic and oligodendroglial tau pathology in terms of tufted astrocytes, thorn-shaped astrocytes, and coiled bodies. Additionally, there were TAR DNA-binding protein 43 (TDP-43) positive cytoplasmic inclusions in the frontal lobe and hippocampus, and Amyloid Precursor Protein (APP) positivity in the axons of the white matter. A systematic review of the literature revealed only 13 other soccer players with postmortem diagnosis of CTE. Our report illustrates the complex clinicopathological correlation of CTE and the need for disease-specific biomarkers.

EEG/ERP evidence of possible hyperexcitability in older adults with elevated beta-amyloid

BackgroundAlthough growing evidence links beta-amyloid (Aβ) and neuronal hyperexcitability in preclinical mouse models of Alzheimer’s disease (AD), a similar association in humans is yet to be established. The first aim of the study was to determine the association between elevated Aβ (Aβ+) and cognitive processes measured by the P3 event-related potential (ERP) in cognitively normal (CN) older adults. The second aim was to compare the event-related power between CNAβ+ and CNAβ−.MethodsSeventeen CNAβ+ participants (age: 73 ± 5, 11 females, Montreal Cognitive Assessment [MoCA] score 26 ± 2) and 17 CNAβ- participants group-matched for age, sex, and MOCA completed a working memory task (n-back with n = 0, 1, 2) test while wearing a 256-channel electro-encephalography net. P3 peak amplitude and latency of the target, nontarget and task difference effect (nontarget−target), and event-related power in the delta, theta, alpha, and beta bands, extracted from Fz, Cz, and Pz, were compared between groups using linear mixed models. P3 amplitude of the task difference effect at Fz and event-related power in the delta band were considered main outcomes. Correlations of mean Aβ standard uptake value ratios (SUVR) using positron emission tomography with P3 amplitude and latency of the task difference effect were analyzed using Pearson Correlation Coefficient r.ResultsThe P3 peak amplitude of the task difference effect at Fz was lower in the CNAβ+ group (P = 0.048). Similarly, power was lower in the delta band for nontargets at Fz in the CNAβ+ participants (P = 0.04). The CNAβ+ participants also demonstrated higher theta and alpha power in channels at Cz and Pz, but no changes in P3 ERP. Strong correlations were found between the mean Aβ SUVR and the latency of the 1-back (r = − 0.69; P = 0.003) and 2-back (r = − 0.69; P = 0.004) of the task difference effect at channel Fz in the CNAβ+ group.ConclusionsOur data suggest that the elevated amyloid in cognitively normal older adults is associated with neuronal hyperexcitability. The decreased P3 task difference likely reflects early impairments in working memory processes. Further research is warranted to determine the validity of ERP in predicting clinical, neurobiological, and functional manifestations of AD.

Kynurenine Pathway Metabolites as Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that deteriorates cognitive function. Patients with AD generally exhibit neuroinflammation, elevated beta-amyloid (Aβ), tau phosphorylation (p-tau), and other pathological changes in the brain. The kynurenine pathway (KP) and several of its metabolites, especially quinolinic acid (QA), are considered to be involved in the neuropathogenesis of AD. The important metabolites and key enzymes show significant importance in neuroinflammation and AD. Meanwhile, the discovery of changed levels of KP metabolites in patients with AD suggests that KP metabolites may have a prominent role in the pathogenesis of AD. Further, some KP metabolites exhibit other effects on the brain, such as oxidative stress regulation and neurotoxicity. Both analogs of the neuroprotective and antineuroinflammation metabolites and small molecule enzyme inhibitors preventing the formation of neurotoxic and neuroinflammation compounds may have potential therapeutic significance. This review focused on the KP metabolites through the relationship of neuroinflammation in AD, significant KP metabolites, and associated molecular mechanisms as well as the utility of these metabolites as biomarkers and therapeutic targets for AD. The objective is to provide references to find biomarkers and therapeutic targets for patients with AD.

Visual paired associate learning deficits associated with elevated beta-amyloid in cognitively normal older adults.

Previous studies have shown that paired associate learning (PAL), a type of episodic memory, is impaired in early Alzheimer's disease (AD). Such tasks require that a set of associations (e.g., pattern-location) be learned over several trials, and the objective is to reduce errors with each trial. Currently, the nature and magnitude of impairment and decline on PAL measures in cognitively normal (CN) older adults with elevated levels of beta-amyloid (Aβ+) is unknown. This study examined PAL errors in Aβ+ and Aβ - CN older adults, both within a single assessment and over time. Participants (210 Aβ - CN, 146 Aβ + CN) from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study underwent three assessments over 36-months (baseline, and 18- and 36-month follow-ups) using a computerized paired associate learning task (CPAL). Aβ status was determined by positron emission tomography (PET) neuroimaging. No significant group differences in PAL were evident at baseline. Significant groupxtime interactions were observed, with the Aβ - CN group, but not the Aβ + CN group, evidencing improvement over time (Cohen's d = 0.30 [0.08, 0.51]). Despite this, no group differences were evident at 36-months. Results suggest that PAL dysfunction is evident over time in Aβ + CNs. This indicates a lack of benefit from repeated exposure to the task over time associated with Aβ+, which is not the case for Aβ - CNs. Further, results suggest that assessing change in Aβ+ related cognition over time, rather than at a single assessment, provides greater understanding of dysfunction in early AD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

CORRELATION OF AGGREGATED BETA AMYLOID LEVEL IN PLASMA WITH MOCA AND MMSE AMONG TYPE 2 DIABETIC PATIENTS WITH DEMENTIA

Type 2 Diabetes Mellitus (DM) as a risk factor for Alzheimer's disease (AD) and decline in cognitive functions have been studied in recent years; however, no clear evidence of association has been found yet. As potential biomarker for AD, aggregated beta amyloid level in plasma is likewise under study by some medical researchers. We examined the correlation between plasma beta amyloid levels and cognitive functions of Type 2 DM patients with Dementia as indicated by their neurocognitive assessment scores with the end in view of finding a less invasive early detection of AD among diabetic patients. In this Cross Sectional study, 100 Type 2 DM patients with dementia (39% male, 68.71 ± 6.9 years) underwent plain cranial CT scan, plasma beta amyloid, Mini Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA) tests. Patients were categorized as having Vascular or Non Vascular Dementia with the use of NINDS-AIREN Criteria for Vascular Dementia. Elevated aggregated beta amyloid level in plasma (≥ 1.1 pg/ml) was used as biomarker for AD. Among Type 2 DM patients with dementia, there was an increased prevalence of AD (46.7%) as shown by the elevated beta amyloid level independent of Vascular Dementia. The prevalence of vascular dementia was 6%. Among patients with Non Vascular Dementia, majority (51.3%) had elevated beta amyloid. There was no significant correlation between MMSE score and beta amyloid (r= - 0.0192, p = 0.8557), while no significant correlation between MoCA score and beta amyloid (r=0.0939, p=0.3731) among Type 2 DM patients with Dementia. The results did not show significant correlation between both MMSE (r=−0.0664, p=0.6725) and MoCA scores (r=- 0.0877, p=0.5759) with beta amyloid level among those patients with AD. Using the beta amyloid as a biomarker, the study suggests a link between AD and Type 2 DM; however, we recommend that further researches be conducted to ascertain the use of aggregated beta amyloid level in plasma as a less invasive screening routine for AD among Type 2 DM patients with dementia.

Synergism between fornix microstructure and beta amyloid accelerates memory decline in clinically normal older adults

The fornix is the primary efferent white matter tract of the hippocampus and is implicated in episodic memory. In this study, we investigated whether baseline measures of altered fornix microstructure and elevated beta amyloid (Aβ) burden influence prospective cognitive decline. A secondary goal examined whether Aβ burden is negatively associated with fornix microstructure. 253 clinically normal older adults underwent diffusion-weighted imaging and Pittsburgh Compound B positron emission tomography at baseline. We applied a novel streamline tractography protocol to reconstruct a fornix bundle in native space. Cognition was measured annually in domains of episodic memory, executive function, and processing speed (median follow-up = 4.0 ± 1.4 years). After controlling for covariates, linear mixed-effects models demonstrated an interaction of fornix microstructure with Aβ burden on episodic memory, such that combined lower fornix microstructure and higher Aβ burden was associated with accelerated decline. By contrast, associations with executive function and processing speed were not significant. There was no cross-sectional association between Aβ burden and fornix microstructure. In conclusion, altered fornix microstructure may accelerate memory decline in preclinical Alzheimer's disease.

Blunted cerebrovascular response is associated with elevated beta-amyloid

The goal of this study was to explore the association of beta-amyloid accumulation and cerebrovascular response (CVR) in cognitively normal older adults. Beta-amyloid accumulation was characterized with [18F] Florbetapir positron emission tomography scans. CVR was calculated as middle cerebral artery blood flow velocity change from rest to moderate intensity exercise. We found that individuals with elevated beta-amyloid aggregation had a blunted CVR (n = 25, age 70.1 ± 4.8; 3.3 ± 3.7 cm/s) compared to non-elevated individuals (n = 45, age 72.0 ± 4.9; 7.2 ± 5.0 cm/s, p < 0.001). Further, greater beta-amyloid burden was linearly associated with less CVR across all participants (b = −11.7, p < 0.001). Greater CVR and less beta-amyloid burden were associated with processing speed (p < 0.05). This study is the first to show that CVR from rest to exercise is blunted across increased global beta-amyloid burden.

Beta-amyloid and Cortical Thickness Reveal Racial Disparities in Preclinical Alzheimer's Disease.

African Americans are two to four times more likely to develop dementia as Non-Hispanic Whites. This increased risk among African Americans represents a critical health disparity that affects nearly 43 million Americans. The present study tested the hypothesis that older African Americans with elevated beta-amyloid would show greater neurodegeneration (smaller hippocampal volumes and decreased cortical thickness) than older Non-Hispanic Whites with elevated beta-amyloid. Data from the Harvard Aging Brain Study (HABS) were used to form a group of older African Americans and two matched groups of Non-Hispanic White adults. Amyloid-positive African Americans had decreased cortical thickness in most of the Alzheimer's disease (AD) signature regions compared with amyloid-positive Non-Hispanic Whites. This factor was negatively correlated with age and white matter hypointensities. Using support vector regression, we also found some evidence that African Americans have an older “brain age” than Non-Hispanic Whites. These findings suggest that African Americans might be more susceptible to factors causing neurodegeneration, which then might accelerate the rate of a diagnosis of AD.

MH84: A Novel γ-Secretase Modulator/PPARγ Agonist--Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer's Disease.

Developing new therapeutic strategies for Alzheimer's disease (AD) is a current challenge. Approved drugs merely act symptomatically and delay the progression of the disease for a relatively short period of time. Here, we investigated the effectiveness of MH84 in a cellular HEK293APPwt model of AD, characterized by elevated beta amyloid protein levels (Aβ1-42) and mitochondrial dysfunction. MH84 is a derivate of pirinixic acid belonging to a novel class of γ-secretase modulators, which combines γ-secretase modulation with activation of peroxisome proliferator-activator receptor gamma (PPARγ). The mitochondria modifying Dimebon, the γ-secretase blocker DAPT, and the PPARγ agonist pioglitazone were used as controls. MH84 protects against nitrosative stress, increased mitochondrial respiration, citrate synthase (CS) activity and protein levels of PGC1α indicating enhanced mitochondrial content at nano-molar concentrations. Concurrently, MH84 decreased protein levels of APP, Aβ1-42, and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular Aβ1-42 levels. Dimebon improved mitochondrial functions and DAPT decreased mitochondrial membrane potential. Pioglitazone had no effects on APP processing and mitochondrial function. Our data emphasizes MH84 as possible novel therapeutic agent with mitochondria-based mode of action.

Comparison of Regional Brain Perfusion Levels in Chronically Smoking and Non-Smoking Adults.

Chronic cigarette smoking is associated with numerous abnormalities in brain neurobiology, but few studies specifically investigated the chronic effects of smoking (compared to the acute effects of smoking, nicotine administration, or nicotine withdrawal) on cerebral perfusion (i.e., blood flow). Predominately middle-aged male (47 ± 11 years of age) smokers (n = 34) and non-smokers (n = 27) were compared on regional cortical perfusion measured by continuous arterial spin labeling magnetic resonance studies at 4 Tesla. Smokers showed significantly lower perfusion than non-smokers in the bilateral medial and lateral orbitofrontal cortices, bilateral inferior parietal lobules, bilateral superior temporal gyri, left posterior cingulate, right isthmus of cingulate, and right supramarginal gyrus. Greater lifetime duration of smoking (adjusted for age) was related to lower perfusion in multiple brain regions. The results indicated smokers showed significant perfusion deficits in anterior cortical regions implicated in the development, progression, and maintenance of all addictive disorders. Smokers concurrently demonstrated reduced blood flow in posterior brain regions that show morphological and metabolic aberrations as well as elevated beta amyloid deposition demonstrated by those with early stage Alzheimer disease. The findings provide additional novel evidence of the adverse effects of cigarette smoking on the human brain.

Anxiety symptoms, cerebral amyloid burden and memory decline in healthy older adults without dementia: 3-year prospective cohort study

Although beta-amyloid, anxiety and depression have linked cross-sectionally to reduced memory function in healthy older adults without dementia, prospective data evaluating these associations are lacking. Using data an observational cohort study of 178 healthy older adults without dementia followed for 3 years, we found that anxiety symptoms significantly moderated the relationship between beta-amyloid level and decline in verbal (Cohen's d = 0.65) and episodic (Cohen's d = 0.38) memory. Anxiety symptoms were additionally linked to greater decline in executive function, irrespective of beta-amyloid and other risk factors. These findings suggest that interventions to mitigate anxiety symptoms may help delay memory decline in otherwise healthy older adults with elevated beta-amyloid.

Relationship between ALS and the degree of cognitive impairment, markers of neurodegeneration and predictors for poor outcome. A prospective study

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease affecting motor neurons and may be associated with impaired cognition. Reliable prognostic factors for ALS patients are still missing. We prospectively included 67 patients, 42 women and 25 men, with clinically defined ALS. The disease severity was assessed and the patients underwent SPECT, lumbar puncture with determination of tau, hyperphosporylated tau (p-tau) and beta-amyloid and a detailed neuropsychological assessment using a standardized test battery. In patients who died, a detailed neuropathologic evaluation was performed. The mean survival duration was 26.8 months. The delay between the first signs and confirmation of the diagnosis was 12.75 months. Cognitive impairment did not have an impact on the evolution of the disease. There was no correlation between neuropsychological and SPECT findings. Higher age at onset, more pronounced handicap and elevated beta-amyloid in the CSF were associated with shorter survival times. In brain tissue from nine of the deceased patients with ALS and dementia, all showed signs of comorbidity, six had hallmarks of frontotemporal lobar degeneration (FTLD) and three showed Alzheimer disease pathology. Brain tissues form 11 deceased ALS patients who did not show signs of dementia, had only changes compatible with a diagnosis of motor neuron disease. In our prospective study, age, disease severity and CSF beta-amyloid levels taken together were a risk factor suggesting shorter survival times. Dementia is relatively frequent in ALS and may be a consequence of either FTLD or result from co-existing Alzheimer disease.

β-Amyloid is Associated with Reduced Cognitive Function in Healthy Older Adults

Though elevated beta-amyloid deposition is associated with Alzheimer's disease, recent evidence suggests beta-amyloid is elevated in healthy older adults prior to the onset of Alzheimer's disease. No study has yet investigated whether reduced cognitive function is related to beta-amyloid elevation in healthy older adults. Thirty-five healthy older adults underwent neuropsychological testing and fasting blood draw with subsequent serum beta-amyloid 1-40 level quantification. beta-amyloid was negatively correlated with several aspects of cognition. Findings indicate that beta-amyloid level is associated with cognitive function in healthy older adults in a pattern similar to early Alzheimer's disease. Further work investigating possible mechanisms is needed.

Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy

Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain's innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated beta-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin (ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-alpha, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic.

The pathological interaction between diabetes and presymptomatic Alzheimer's disease

Since diabetes is a risk factor for Alzheimer's disease (AD), we asked if there is a functional interaction between high glucose and elevated beta amyloid peptide (Aβ) in cultured brain microvascular endothelial cells and presymptomatic AD transgenic mice. When cultured brain microvascular endothelial cells are exposed to both high glucose and low levels of Aβ, there is a synergistic interaction to cause an increased accumulation of advanced glycation products (AGE) and reactive oxygen species (ROS). When presymptomatic mice expressing mutant human amyloid precursor protein and presenilin are made diabetic, they have a decrease in cognitive function relative to control mice. Associated with the cognitive deficit are increases in brain microvascular AGE and iNOS expression, and the loss of the synaptic spine protein drebrin. No amyloid plaques or tangles are observed within the brains of any group. These data show that diabetes causes a synergistic potentiation of some indices of AD in transgenic animals that are presymptomatic for the classical features of the disease.

Reduction of sortilin-1 in Alzheimer hippocampus and in cytokine-stressed human brain cells

Sortilin 1 (SORL1) is a transmembrane sorting receptor that regulates the intracellular trafficking of beta-amyloid precursor protein (betaAPP). Interactions between SORL1 and betaAPP result in the decreased processing of betaAPP into toxic amyloid-beta42 (Abeta42) peptides that accumulate in Alzheimer's disease brain. Here, we report selectively decreased levels of SORL1 in limbic and occipital regions of Alzheimer brain that inversely correlate with amyloid plaque and neurofibrillary tangle density. Reduced SORL1, coupled to elevated beta-amyloid cleaving enzyme, presenilin-1 and increased Abeta42 peptide secretion, was observed after incubation of cultured human neural cells with the proinflammatory cytokine interleukin-1beta. The results suggest that SORL1 deficits may not only promote the pathogenic processing of betaAPP but may also contribute to Abeta42-mediated inflammatory signaling in stressed human brain cells.

Signals Modulating p‐Glycoprotein Activity in Brain Capillaries

At the blood-brain barrier, p-glycoprotein, an ATP-driven efflux pump, limits drug entry into the brain and thus CNS pharmacotherapy. We have identified multiple extracellular and intracellular signals that regulate this transporter. Eight signaling pathways have been defined and partially mapped. Three pathways are triggered by elements of the brain’s innate immune response, one by reactive oxygen species, one by glutamate, one by drug-nuclear receptor (PXR) interactions and two by elevated beta-amyloid levels. Three work over the short-term (minutes) to reduce transport function with no change in transporter expression. Five work over the long-term (hours to days). Of these, four increase both function and expression and one decreases function and expression. Signaling is complex, with several pathways having common signaling elements (TNF-R1, ET-B receptor, protein kinase C, NO synthase), suggesting a regulatory network. Several pathways utilize autocrine/paracrine elements, involving release of the pro-inflammatory cytokine, TNF-alpha, and the polypeptide hormone, endothelin. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate p-glycoprotein activity.