Amyloid-β Changes Research Articles

Body Mass Index Decrease Has a Distinct Association with Alzheimer's Disease Pathophysiology in APOE ɛ4 Carriers and Non-Carriers.

Body mass index (BMI) changes may be related to Alzheimer's disease (AD) alterations, but it is unclear how the apolipoprotein E ɛ4 (APOE ɛ4) allele affects their association. To explore the association of BMI changes with AD pathologies in APOE ɛ4 carriers and non-carriers. In 862 non-demented ADNI participants with≥2 BMI measurements, we investigated the relationships between BMI slopes and longitudinal changes in amyloid-β (Aβ) accumulation, neurodegeneration and cognition, and follow-up tau deposition in different Aβ and APOE ɛ4 statuses. In Aβ+ APOE ɛ4 non-carriers, faster BMI declines were associated with faster rates of Aβ accumulation (standardized β (βstd) = -0.29, p = 0.001), AD meta regions of interest (metaROI) hypometabolism (βstd = 0.23, p = 0.026), memory declines (βstd = 0.17, p = 0.029), executive function declines (βstd = 0.19, p = 0.011), and marginally faster Temporal-metaROI cortical thinning (βstd = 0.15, p = 0.067) and higher follow-up Temporal-metaROI tau deposition (βstd = -0.17, p = 0.059). Among Aβ- individuals, faster BMI decreases were related to faster Aβ accumulation (βstd = -0.25, p = 0.023) in APOE ɛ4 carriers, whereas predicted faster declines in memory and executive function in both APOE ɛ4 carriers (βstd = 0.25, p = 0.008; βstd = 0.32, p = 0.001) and APOE ɛ4 non-carriers (βstd = 0.11, p = 0.030; βstd = 0.12, p = 0.026). This study highlights the significance of tracking BMI data in older adults by providing novel insights into how body weight fluctuations and APOE ɛ4 interact with AD pathology and cognitive decline.

Mechanisms behind changes of neurodegeneration biomarkers in plasma induced by sleep deprivation.

Acute sleep deprivation has been shown to affect cerebrospinal fluid and plasma concentrations of biomarkers associated with neurodegeneration, though the mechanistic underpinnings remain unknown. This study compared individuals who, for one night, were either subject to total sleep deprivation or free sleep, (i) examining plasma concentrations of neurodegeneration biomarkers the morning after sleep deprivation or free sleep and (ii) determining how overnight changes in biomarkers plasma concentrations correlate with indices of meningeal lymphatic and glymphatic clearance functions. Plasma concentrations of amyloid-β 40 and 42, phosphorylated tau peptide 181, glial fibrillary acid protein and neurofilament light were measured longitudinally in subjects who from Day 1 to Day 2 either underwent total sleep deprivation (n = 7) or were allowed free sleep (n = 21). The magnetic resonance imaging contrast agent gadobutrol was injected intrathecally, serving as a cerebrospinal fluid tracer. Population pharmacokinetic model parameters of gadobutrol cerebrospinal fluid-to-blood clearance were utilized as a proxy of meningeal lymphatic clearance capacity and intrathecal contrast-enhanced magnetic resonance imaging as a proxy of glymphatic function. After one night of acute sleep deprivation, the plasma concentrations of amyloid-β 40 and 42 were reduced, but not the ratio, and concentrations of the other biomarkers were unchanged. The overnight change in amyloid-β 40 and 42 plasma concentrations in the sleep group correlated significantly with indices of meningeal lymphatic clearance capacity, while this was not seen for the other neurodegeneration biomarkers. However, overnight change in plasma concentrations of amyloid-β 40 and 42 did not correlate with the glymphatic marker. On the other hand, the overnight change in plasma concentration of phosphorylated tau peptide 181 correlated significantly with the marker of glymphatic function in the sleep deprivation group but not in the sleep group. The present data add to the evidence of the role of sleep and sleep deprivation on plasma neurodegeneration concentrations; however, the various neurodegeneration biomarkers respond differently with different mechanisms behind sleep-induced alterations in amyloid-β and tau plasma concentrations. Clearance capacity of meningeal lymphatics seems more important for sleep-induced changes in amyloid-β 40 and 42 plasma concentrations, while glymphatic function seems most important for change in plasma concentration of phosphorylated tau peptide 181 during sleep deprivation. Altogether, the present data highlight diverse mechanisms behind sleep-induced effects on concentrations of plasma neurodegeneration biomarkers.

Effect of Pathway-Specific Polygenic Risk Scores for Alzheimer's Disease (AD) on Rate of Change in Cognitive Function and AD-Related Biomarkers Among Asymptomatic Individuals.

Genetic scores for late-onset Alzheimer's disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer's Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample. We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-β, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-β, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-β and tau, long before the onset of clinical symptoms.

Potential association of bone mineral density loss with cognitive impairment and central and peripheral amyloid-β changes: a cross-sectional study

BackgroundThere is some evidence in the literature that older adults with cognitive impairments have a higher risk for falls and osteoporotic hip fractures. Currently, the associations between bone health and cognitive health have not been extensively studied. Thus, the present cross-sectional study aims to investigate the relationship between markers of bone loss and cognitive performance in older adults with and without osteopenia as well as older adults with cognitive impairments (i.e., Alzheimer’s disease [AD]).MethodsSixty-two non-osteopenia participants and one hundred three osteopenia participants as the cohort 1 and 33 cognitively normal non-AD participants and 39 AD participants as the cohort 2 were recruited. To assess cognitive and bone health, hip bone mineral density (BMD) and cognitive performance (via Minimal Mental State Examination [MMSE] and/or Auditory Verbal Learning Test-delayed recall [AVLT-DR]) were assessed. Furthermore, in cohort 1, plasma amyloid-β (Aβ) levels, and in cohort 2, cerebrospinal fluid (CSF) Aβ levels were determined.ResultsWe observed that (1) compared with non-osteopenia participants, BMD values (t = − 22.806; 95%CI: − 1.801, − 1.484; p < 0.001), MMSE scores (t = − 5.392; 95%CI: − 3.260, − 1.698; p < 0.001), and AVLT-DR scores (t = − 4.142; 95%CI: − 2.181, − 0.804; p < 0.001), plasma Aβ42 levels (t = − 2.821; 95%CI: − 1.737, − 0.305; p = 0.01), and Aβ42/40 ratio (t = − 2.020; 95%CI: − 0.009, − 0.001; p = 0.04) were significantly lower in osteopenia participants; (2) plasma Aβ42/40 ratio showed a mediate effect for the association between BMD values and the performance of cognitive function in osteopenia participants by mediation analysis, adjusting age, sex, years of education, and body mass index (BMI); (3) BMD values (95%CI: − 1.085, 0.478; p < 0.001) were significantly reduced in AD participants as compared with cognitively normal non-AD participants; (4) in AD participants, the interactive effects of BMD and CSF Aβ42/40 ratio on MMSE scores was found by regression analysis, controlling age, sex, years of education, and BMI; (5) BMD can distinguish AD participants from cognitively normal non-AD participants with AUC of 0.816 and distinguish participants with the cognitive impairment from cognitively normal participants with AUC of 0.794.ConclusionOur findings suggest a relationship between bone health and cognitive health. Given the correlations between BMD and important markers of cognitive health (e.g., central and peripheral pathological change of Aβ), BMD might serve as a promising and easy-accessible biomarker. However, more research is needed to further substantiate our findings.

Deferoxamine reduces amyloid-beta peptides genesis and alleviates neural apoptosis after traumatic brain injury.

Traumatic brain injury (TBI) is recognized as the most influential risk factor for neurodegenerative diseases later in life, including Alzheimer's disease. The aberrant genesis of amyloid-β peptides, which is triggered by TBI, is associated with the development of Alzheimer's disease. Evidence suggests that iron plays a role in both the production of amyloid-β and its neurotoxicity, and iron overload has been noted in the brain after TBI. We therefore investigated the effects of an iron-chelating treatment on amyloid-β genesis in a weight-drop model of TBI in mice. Human brain samples were obtained from patients undergoing surgery for severe brain trauma. The Institute of Cancer Research mice were treated with deferoxamine by intraperitoneal injection after TBI induction. Changes in amyloid-β(1-42) were assessed using western blot and immunohistochemical staining. Ferritin was also detected using western blot to investigate iron deposition in the mice brain. Immunofluorescent terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was also performed to evaluate neural apoptosis. The amyloid-β(1-42) was markedly elevated after TBI in both humans and mice. Deferoxamine treatment in mice significantly decreased the levels of both amyloid-β(1-42) and ferritin in the brain, and reduced TBI-induced neural cell apoptosis. The iron chelator deferoxamine can alleviate the increase of amyloid-β(1-42) in the brain after TBI, and may therefore be a potential therapeutic strategy to prevent TBI patients from undergoing neurodegenerative processes.

Structural Changes in Amyloid-β by Binding to Glycan Clusters

Structural Changes in Amyloid-β by Binding to Glycan Clusters

Multifunctionalized Reduced Graphene Oxide Biosensors for Simultaneous Monitoring of Structural Changes in Amyloid-β 40.

Determination of the conformation (monomer, oligomer, or fibril) of amyloid peptide aggregates in the human brain is essential for the diagnosis and treatment of Alzheimer’s disease (AD). Accordingly, systematic investigation of amyloid conformation using analytical tools is essential for precisely quantifying the relative amounts of the three conformations of amyloid peptide. Here, we developed a reduced graphene oxide (rGO) based multiplexing biosensor that could be used to monitor the relative amounts of the three conformations of various amyloid-β 40 (Aβ40) fluids. The electrical rGO biosensor was composed of a multichannel sensor array capable of individual detection of monomers, oligomers, and fibrils in a single amyloid fluid sample. From the performance test of each sensor, we showed that this method had good analytical sensitivity (1 pg/mL) and a fairly wide dynamic range (1 pg/mL to 10 ng/mL) for each conformation of Aβ40. To verify whether the rGO biosensor could be used to evaluate the relative amounts of the three conformations, various amyloid solutions (monomeric Aβ40, aggregated Aβ40, and disaggregated Aβ40 solutions) were employed. Notably, different trends in the relative amounts of the three conformations were observed in each amyloid solution, indicating that this information could serve as an important parameter in the clinical setting. Accordingly, our analytical tool could precisely detect the relative amounts of the three conformations of Aβ40 and may have potential applications as a diagnostic system for AD.

Dissociation of cerebrospinal fluid amyloid-β and tau levels in patients with prolonged posttraumatic disorders of consciousness

ABSTRACTBackground: Traumatic brain injury (TBI) is a major risk factor for Alzheimer’s disease (AD). Although the mechanisms that lead to AD after a TBI are unclear, we hypothesize that changes in amyloid-β (Aβ) metabolism and abnormal tau phosphorylation are reasonable candidates.Objective: To investigate Aβ and tau dynamics in the chronic phase of TBI.Methods: We evaluated Aβ1-42, total tau (t-tau), and phosphorylated tau (p-tau) levels in the cerebrospinal fluid (CSF) of 15 patients who developed a prolonged disorder of consciousness after a severe TBI (mean time from TBI 271.6 ± 176.5 days).Results: Reduced Aβ1-42 levels (median 258 pg/ml, range 90–833.6) were observed in 14/15 patients (93.3%) with severe post-TBI disorders of consciousness. These CSF analysis data did not correlate with time since TBI or with the patients’ level of consciousness as determined by the Coma Recovery Scale Revised. Normal t-tau levels (median 95.2 pg/ml, range 52–256.9) were found in all patients. Normal p-tau levels (median 22.2 pg/ml, range 14–72) were observed in 14/15 patients, with just a single patient having a slightly increased p-tau level.Conclusion: The present findings show that Aβ and tau are differently affected in the chronic phase of severe TBI.

Data-driven models of dominantly-inherited Alzheimer's disease progression.

See Li and Donohue (doi:10.1093/brain/awy089) for a scientific commentary on this article.Dominantly-inherited Alzheimer's disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer's disease. We use emerging techniques in generative data-driven disease progression modelling to characterize dominantly-inherited Alzheimer's disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset. We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers in three subtypes: 163 PSEN1, 17 PSEN2, and 31 APP) and a baseline visit (age 19-66; up to four visits each, 1.1 ± 1.9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then subcortical regions (∼24 ± 11 years before onset); phosphorylated tau (17 ± 8 years), tau and amyloid-β changes in cerebrospinal fluid; neurodegeneration first in the putamen and nucleus accumbens (up to 6 ± 2 years); then cognitive decline (7 ± 6 years), cerebral hypometabolism (4 ± 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than predictions that used familial estimates: root mean squared error of 1.35 years versus 5.54 years. The models reveal hidden detail on dominantly-inherited Alzheimer's disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials.

38. Different behavior of cerebrospinal fluid amyloid-[formula omitted] and tau levels in patients with post-traumatic disorders of consciousness

Traumatic brain injury (TBI) is a major risk factor for Alzheimer disease (AD). Although the mechanisms that lead to AD after a TBI are largely unknown, changes in amyloid-β (Aβ) metabolism and abnormal tau phosphorylation are probably involved. In this study, we evaluated Aβ1-42, total tau (t-tau), and phosphorylated tau (p-tau) levels in the cerebrospinal fluid (CSF) of 15 patients who developed a prolonged disorder of consciousness after a severe TBI (mean time from TBI 271.6 ± 176.5 days; range 92–578 days). Reduced Aβ1-42 levels (cohort median value 258 pg/ml, range 90–833.6 pg/ml) were observed in 14/15 patients (93.3%) with severe post-TBI disorders of consciousness. Normal t-tau levels (median 95.2 pg/ml, range 52–256.9 pg/ml) were found in all patients. Normal p-tau levels (median 22.2 pg/ml, range 14–72 pg/ml) were observed in 14/15 patients, while 1 patient had a p-tau level slightly increased. In conclusion, the present findings show that reduced CSF Aβ levels are not paralleled by significant changes in t-tau and p-tau levels; these results suggest that treatments aimed to prevent chronic neurodegeneration and AD risk after a severe TBI may be better targeted on Aβ than tau.

THE RELATIONSHIP BETWEEN CSF AMYLOID BETA CONCENTRATIONS AND FREE AND CUED RECALL PERFORMANCE AMONG PARTICIPANTS WITH AMNESTIC MILD COGNITIVE IMPAIRMENT

Alzheimer's Disease (AD) is a neurodegenerative disease which typically presents with a specific episodic memory impairment. Although accumulation of hypertphosphoryllated tau is held responsible for the neurodegeneration and hence the symptoms of AD, recent research suggests that changes in amyloid-β (Aβ) 1−42 concentrations might also be related to memory performance. We aimed to investigate whether cerebro-spinal fluid (CSF) Aβ42 concentrations are related to free and cued recall performance among a group of patients with amnestic type MCI. The results that will be presented here are part of a still ongoing research project. Currently, we have 18 participants diagnosed with amnestic type MCI. All participants underwent an extended procedure involving neurological examination, multimodal neuroimaging, neuropsychological assessment, and lumbar puncture for CSF biomarkers. Free and Cued Selective Reminding Test was used as the principal measure to assess memory performance. The CSF Aβ42 concentrations of the sample ranged between 299 and 1377 pg/mL. Based on their Aβ concentration, we assigned the sample into two groups: low Aβ group (n=9) and high Aβ group (n=9). The cutoff value was 850 pg/mL. Then, 2 groups were compared with regard to their FCSRT scores. Significant intergroup differences were found with regard to total free recall performance. Specifically, high-amyloid group had significantly higher total free recall scores than low amyloid group (U= 14.00, p<.05). On the other hand, with respect to cue index scores, which an indicator of how each participant is able to benefit from cues, there was not a statistically significant difference between the two groups. Our initial results suggest that reduced CSF Aβ42 concentrations might interfere with free recall performance. The fact that no significant relationship was found with regard to cued recall (which is a specific feature of AD amnesia) might suggest that Aβ42-related amnesia is different from tau-related one, which disconnects entorhinal cortex from the hippocampal formation initially and hence gives rise to typical amnesia (hippocampal-type) that does not improve with cuing. Functional disconnections due to Aβ42 accumulation within a larger network, such as default mode (DMN) is likely to underline such a non-hypocampal-type memory deficit.

Optimal Reference Region to Measure Longitudinal Amyloid-β Change with 18F-Florbetaben PET

Accurate measurement of changes in amyloid-β (Aβ) deposition over time is important in longitudinal studies, particularly in anti-Aβ therapeutic trials. To achieve this, the optimal reference region (RR) must be selected to reduce variance of Aβ PET measurements, allowing early detection of treatment efficacy. The aim of this study was to determine the RR that allows earlier detection of subtle Aβ changes using 18F-florbetaben PET. Methods: Forty-five patients with mild cognitive impairment (mean age ± SD, 72.69 ± 6.54 y; 29 men/16 women) who underwent up to 3 18F-florbetaben scans were included. Baseline scans were visually classified as high (Aβ+) or low (Aβ-) amyloid. Six cortical regions were quantified using a standardized region-of-interest atlas applied to the spatially normalized gray matter image obtained from segmentation of the baseline T1-weighted volumetric MRI. Four RRs (cerebellar gray matter [CGM], whole cerebellum [WCER], pons, and subcortical white matter [SWM]) were studied. The SUV ratio (SUVR) for each RR was calculated by dividing cortex activity by RR activity, with a composite SUVR averaged over 6 cortical regions. SUVR increase from baseline to 1 and 2 y, and percentage Aβ deposition per year, were assessed across Aβ+ and Aβ- groups. Results: SUVs for any RR were not significantly different over time. Percentage Aβ accumulation per year derived from composite SUVR was 0.10 ± 1.72 (Aβ-) and 1.36 ± 1.98 (Aβ+) (P = 0.02) for CGM and 0.13 ± 1.47 and 1.32 ± 1.75 (P = 0.01), respectively, for WCER. Compared with baseline, the composite SUVR increase in Aβ+ scans was significantly larger than in Aβ- scans at 1 y (P = 0.04 [CGM]; P = 0.03 [WCER]) and 2 y (P = 0.02 [CGM]; P = 0.01 [WCER]) using these 2 RRs. Significant SUVR changes using the pons as the RR were detected only at 2 y (P = 0.46 [1 y], P = 0.001 [2 y]). SUVR using the SWM as the RR showed no significant differences at either follow-up (P = 0.39 [1 y], P = 0.09 [2 y]). Conclusion: RR selection influences reliable early measurement of Aβ changes over time. Compared with SWM and pons, which do not fulfil the RR requirements and have limited sensitivity to detect Aβ changes, cerebellar RRs are recommended for 18F-florbetaben PET because they allow earlier detection of Aβ accumulation.

Amyloid burden and incident depressive symptoms in cognitively normal older adults.

Several studies have reported that non-demented older adults with clinical depression show changes in amyloid-β (Aβ) levels in blood, cerebrospinal fluid and on neuroimaging that are consistent with those observed in patients with Alzheimer's disease. These findings suggest that Aβ may be one of the mechanisms underlying the relation between the two conditions. We sought to determine the relation between elevated cerebral Aβ and the presence of depression across a 54-month prospective observation period. Cognitively normal older adults from the Australian Imaging Biomarkers and Lifestyle study who were not depressed and had undergone a positron emission tomography scan to classify them as either high Aβ (n = 81) or low Aβ (n = 278) participated. Depressive symptoms were assessed using the Geriatric Depression Scale - Short Form at 18-month intervals over 54 months. Whilst there was no difference in probable depression between groups at baseline, incidence was 4.5 (95% confidence interval [CI] 1.3-16.4) times greater within the high Aβ group (9%) than the low Aβ group (2%) by the 54-month assessment. Results of this study suggest that elevated Aβ levels are associated with a 4.5-fold increased likelihood of developing clinically significant depressive symptoms on follow-up in preclinical Alzheimer's disease. This underscores the importance of assessing, monitoring and treating depressive symptoms in older adults with elevated Aβ. Copyright © 2016 John Wiley & Sons, Ltd.

Antidiabetic drugs restore abnormal transport of amyloid-β across the blood–brain barrier and memory impairment in db/db mice

Previous studies have shown significant changes in amyloid-β (Aβ) transport across the blood–brain barrier (BBB) under diabetic conditions with hypoinsulinemia, which is involved in diabetes-associated cognitive impairment. Present study employed db/db mice with hyperinsulinemia to investigate changes in Aβ transport across the BBB, hippocampal synaptic plasticity, and restorative effects of antidiabetic drugs. Our results showed that db/db mice exhibited similar changes in Aβ transport across the BBB to that of insulin-deficient mice. Chronic treatment of db/db mice with antidiabetic drugs such as metformin, glibenclamide and insulin glargine significantly decreased Aβ influx across the BBB determined by intra-arterial infusion of 125I-Aβ1-40, and expression of the receptor for advanced glycation end products (RAGE) participating in Aβ influx. Insulin glargine, but not, metformin or glibenclamide increased Aβ efflux across the BBB determined by stereotaxic intra-cerebral infusion of 125I-Aβ1-40, and expression of the low-density lipoprotein receptor related protein 1 (LRP1) participating in Aβ efflux. Moreover, treatment with these drugs significantly decreased hippocampal Aβ1-40 or Aβ1-42 and inhibited neuronal apoptosis. The drugs also ameliorated memory impairment confirmed by improved performance on behavioral tasks. However, insulin glargine or glibenclamide, but not metformin, restored hippocampal synaptic plasticity characterized by enhancing in vivo long-term potentiation (LTP). Further study found that these three drugs significantly restrained NF-κB, but only insulin glargine enhanced peroxisome proliferator-activated receptor γ (PPARγ) activity at the BBB in db/db mice. Our data indicate that the antidiabetic drugs can partially restore abnormal Aβ transport across the BBB and memory impairment under diabetic context.

Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo.

Epidemiological studies show that patients with type 2 diabetes (T2DM) and individuals with a diabetes-independent elevation in blood glucose have an increased risk for developing dementia, specifically dementia due to Alzheimer's disease (AD). These observations suggest that abnormal glucose metabolism likely plays a role in some aspects of AD pathogenesis, leading us to investigate the link between aberrant glucose metabolism, T2DM, and AD in murine models. Here, we combined two techniques – glucose clamps and in vivo microdialysis – as a means to dynamically modulate blood glucose levels in awake, freely moving mice while measuring real-time changes in amyloid-β (Aβ), glucose, and lactate within the hippocampal interstitial fluid (ISF). In a murine model of AD, induction of acute hyperglycemia in young animals increased ISF Aβ production and ISF lactate, which serves as a marker of neuronal activity. These effects were exacerbated in aged AD mice with marked Aβ plaque pathology. Inward rectifying, ATP-sensitive potassium (K(ATP)) channels mediated the response to elevated glucose levels, as pharmacological manipulation of K(ATP) channels in the hippocampus altered both ISF Aβ levels and neuronal activity. Taken together, these results suggest that K(ATP) channel activation mediates the response of hippocampal neurons to hyperglycemia by coupling metabolism with neuronal activity and ISF Aβ levels.

Changes in Amyloid-β and Tau in the Cerebrospinal Fluid of Transgenic Mice Overexpressing Amyloid Precursor Protein

Altered concentrations of amyloid-β (Aβ) peptide and Tau protein in the cerebrospinal fluid (CSF) are thought to be predictive markers for Alzheimer's disease (AD). Transgenic mice overexpressing human amyloid precursor protein (APP) have been used to model Aβ pathology, but concomitant changes in Aβ and Tau in CSF have been less well studied. We measured Aβ and Tau in the brains and CSF of two well-characterized transgenic mouse models of AD: one expressing human APP carrying the Swedish mutation (APP23) and the other expressing mutant human APP and mutant human presenilin-1 (APPPS1). Both mouse models exhibit Aβ deposition in the brain, but with different onset and progression trajectories. We found an age-related 50 to 80% decrease in Aβ42 peptide in mouse CSF and a smaller decrease in Aβ40, both inversely correlated with the brain Aβ load. Surprisingly, the same mice showed a threefold increase in total endogenous murine Tau in CSF at the stages when Aβ pathology became prominent. The results mirror the temporal sequence and magnitude of Aβ and Tau changes in the CSF of patients with sporadic and dominantly inherited AD. This observation indicates that APP transgenic mice may be useful as a translational tool for predicting changes in Aβ and Tau markers in the CSF of AD patients. These findings also suggest that APP transgenic mouse models may be useful in the search for new disease markers for AD.

Intraneuronal tau aggregation precedes diffuse plaque deposition, but amyloid-β changes occur before increases of tau in cerebrospinal fluid

In comparison to the levels in age and gender-matched controls, reduced levels of pathological amyloid-β protein in cerebrospinal fluid routinely precede the onset of Alzheimer's disease-related symptoms by several years, whereas elevated soluble abnormal tau fractions (phosphorylated tau, total tau protein) in cerebrospinal fluid are detectable only with the onset and progression of clinical symptoms. This sequence of events in cerebrospinal fluid (amyloid-β changes detectable prior to abnormal tau changes) contrasts with that in which both proteins develop in the brain, where intraneuronal tau inclusions (pretangles, neurofibrillary tangles, neuropil threads) appear decades before the deposition of amyloid-β plaques (diffuse plaques, neuritic plaques). This viewpoint attempts to address questions arising in connection with this apparent sequential discrepancy-questions and issues for which there are currently no clear-cut answers.

Detecting amyloid biomarkers: Embodied risk and Alzheimer prevention

The assumption of a rapidly spreading ‘epidemic’ of Alzheimer's disease (AD), the result of aging populations worldwide, coupled with no effective medication for this condition, has incited a move to bring about the prevention of AD before the appearance of clinical symptoms. The following discussion details the establishment of a research conglomerate designed to prevent AD by means of the systematic detection of biomarker changes in healthy middle-aged or younger people. Among the biomarkers currently being standardized are changes in amyloid-β in cerebrospinal fluid (CSF), and deposition of amyloid-β plaques in the living brain detectable by means of brain scans. Possession of one specific allele of the APOE gene is an additional biomarker. However, these molecular features are merely indicators of increased risk, and pre-symptomatic dementia cannot be definitively diagnosed on the basis of the presence of one or more of them. The composition, distribution, and function of the key molecule being tracked, amyloid-β, remains poorly understood and, highly significant, a large number of individuals with a heavy amyloid load in their brains live to old age with no behavioral signs of dementia. The concluding section considers preparations for a randomized controlled trial designed to detect and eliminate amyloid-β deposition very early in its formation.

Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory. Levels of BDNF and its main receptor TrkB (TrkB.TK) have been reported to be decreased while the levels of the truncated TrkB (TrkB.T1) are increased in Alzheimer's disease. We show here that incubation with amyloid-β increased TrkB.T1 receptor levels and decreased TrkB.TK levels in primary neurons. In vivo, APPswe/PS1dE9 transgenic mice (APdE9) showed an age-dependent relative increase in cortical but not hippocampal TrkB.T1 receptor levels compared with TrkB.TK. To investigate the role of TrkB isoforms in Alzheimer's disease, we crossed AP mice with mice overexpressing the truncated TrkB.T1 receptor (T1) or the full-length TrkB.TK isoform. Overexpression of TrkB.T1 in APdE9 mice exacerbated their spatial memory impairment while the overexpression of TrkB.TK alleviated it. These data suggest that amyloid-β changes the ratio between TrkB isoforms in favor of the dominant-negative TrkB.T1 isoform both in vitro and in vivo and supports the role of BDNF signaling through TrkB in the pathophysiology and cognitive deficits of Alzheimer's disease.