Associations between locus coeruleus integrity and nocturnal awakenings in the context of Alzheimer’s disease plasma biomarkers: a 7T MRI study

Abstract Background The brainstem locus coeruleus (LC) constitutes the intersection of the initial pathophysiological processes of Alzheimer’s disease (AD) and sleep-wake dysregulation in the preclinical stages of the disease. However, the interplay between in vivo assessment of LC degeneration and AD-related sleep alterations remains unknown. Here, we sought to investigate whether MRI-assessed LC structural integrity relates to subjective sleep-wake measures in the context of AD plasma biomarkers, in cognitively unimpaired older individuals. Methods Seventy-two cognitively unimpaired older individuals aged 50–85 years (mean age = 65.2 ± 8.2 years, 37 women, 21 APOE ε4 carriers) underwent high-resolution imaging of the LC at 7 Tesla, and LC structural integrity was quantified using a data-driven approach. Reports on habitual sleep quality and nocturnal awakenings were collected using sleep questionnaires. Plasma levels of total tau, p-tau181, Aβ40, and Aβ42 were measured using single-molecule array technology. Results Intensity-based cluster analyses indicated two distinct LC segments, with one covering the middle-to-caudal LC and displaying lower intensity compared to the middle-to-rostral cluster (t70 = −5.12, p < 0.0001). After correction for age, sex, depression, and APOE status, lower MRI signal intensity within the middle-to-caudal LC was associated with a higher number of self-reported nocturnal awakenings (F1,63 = 6.73, pFDR = 0.03). Furthermore, this association was mostly evident in individuals with elevated levels of total tau in the plasma (F1,61 = 4.26, p = 0.04). Conclusion Our findings provide in vivo evidence that worse LC structural integrity is associated with more frequent nocturnal awakenings in the context of neurodegeneration, in cognitively unimpaired older individuals. These results support the critical role of the LC for sleep-wake regulation in the preclinical stages of AD and hold promises for the identification of at-risk populations for preventive interventions.

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Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease

Cell Death and Differentiation ◽

10.1038/s41418-020-00685-9 ◽

2021 ◽

Author(s):

Wen-Dai Bao ◽

Pei Pang ◽

Xiao-Ting Zhou ◽

Fan Hu ◽

Wan Xiong ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Impairment ◽

Iron Homeostasis ◽

Critical Role ◽

Gene Set Enrichment Analysis ◽

Molecular Characteristics ◽

Intracellular Iron

AbstractIron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

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Microtubule affinity–regulating kinase 4 with an Alzheimer's disease-related mutation promotes tau accumulation and exacerbates neurodegeneration

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.014420 ◽

2020 ◽

Vol 295 (50) ◽

pp. 17138-17147

Author(s):

Toshiya Oba ◽

Taro Saito ◽

Akiko Asada ◽

Sawako Shimizu ◽

Koichi M. Iijima ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

De Novo ◽

Elevated Risk ◽

Protein Tau ◽

Function Mechanism ◽

Total Tau ◽

Oligomeric Forms

Accumulation of the microtubule-associated protein tau is associated with Alzheimer's disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser-262 and Ser-356 plays critical roles in tau accumulation and toxicity. Microtubule affinity–regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double de novo mutation in the linker region of MARK4, ΔG316E317D, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4ΔG316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356–dependent and –independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that coexpression of MARK4wt and MARK4ΔG316E317D increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4ΔG316E317D had more potent effects than MARK4wt. Interestingly, the in vitro kinase activities of MARK4wt and MARK4ΔG316E317D were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4ΔG316E317D did. Both MARK4wt and MARK4ΔG316E317D increased the levels of oligomeric forms of tau; however, only MARK4ΔG316E317D further increased the detergent insolubility of tau in vivo. Together, these findings suggest that MARK4ΔG316E317D increases tau levels and exacerbates tau toxicity via a novel gain-of-function mechanism and that modification in this region of MARK4 may affect disease pathogenesis.

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[P3-395]: USING NEUROMELANIN-SENSITIVE MRI TO CHARACTERISE THE STRUCTURAL INTEGRITY OF THE HUMAN LOCUS COERULEUS AT DIFFERENT STAGES OF ALZHEIMER's DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.1611 ◽

2017 ◽

Vol 13 (7S_Part_23) ◽

pp. P1114-P1114

Author(s):

Matthew J. Betts ◽

Arturo Cardenas-Blanco ◽

Martin Kanowski ◽

Annika Spottke ◽

Stefan J. Teipel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Locus Coeruleus ◽

Structural Integrity

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Loss of Hsp110 Leads to Age-Dependent Tau Hyperphosphorylation and Early Accumulation of Insoluble Amyloid β

Molecular and Cellular Biology ◽

10.1128/mcb.01493-09 ◽

2010 ◽

Vol 30 (19) ◽

pp. 4626-4643 ◽

Cited By ~ 41

Author(s):

Binnur Eroglu ◽

Demetrius Moskophidis ◽

Nahid F. Mivechi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Critical Role ◽

Amyloid Β ◽

Tau Phosphorylation ◽

Critical Function ◽

App Processing ◽

Phosphorylation State ◽

Brain Extracts

ABSTRACT Accumulation of tau into neurofibrillary tangles is a pathological consequence of Alzheimer's disease and other tauopathies. Failures of the quality control mechanisms by the heat shock proteins (Hsps) positively correlate with the appearance of such neurodegenerative diseases. However, in vivo genetic evidence for the roles of Hsps in neurodegeneration remains elusive. Hsp110 is a nucleotide exchange factor for Hsp70, and direct substrate binding to Hsp110 may facilitate substrate folding. Hsp70 complexes have been implicated in tau phosphorylation state and amyloid precursor protein (APP) processing. To provide evidence for a role for Hsp110 in central nervous system homeostasis, we have generated hsp110 − / − mice. Our results show that hsp110 − / − mice exhibit accumulation of hyperphosphorylated-tau (p-tau) and neurodegeneration. We also demonstrate that Hsp110 is in complexes with tau, other molecular chaperones, and protein phosphatase 2A (PP2A). Surprisingly, high levels of PP2A remain bound to tau but with significantly reduced activity in brain extracts from aged hsp110 − / − mice compared to brain extracts from wild-type mice. Mice deficient in the Hsp110 partner (Hsp70) also exhibit a phenotype comparable to that of hsp110 − / − mice, confirming a critical role for Hsp110-Hsp70 in maintaining tau in its unphosphorylated form during aging. In addition, crossing hsp110 − / − mice with mice overexpressing mutant APP (APPβsw) leads to selective appearance of insoluble amyloid β42 (Aβ42), suggesting an essential role for Hsp110 in APP processing and Aβ generation. Thus, our findings provide in vivo evidence that Hsp110 plays a critical function in tau phosphorylation state through maintenance of efficient PP2A activity, confirming its role in pathogenesis of Alzheimer's disease and other tauopathies.

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Relationship between cortical iron and tau aggregation in Alzheimer’s disease

Brain ◽

10.1093/brain/awaa089 ◽

2020 ◽

Vol 143 (5) ◽

pp. 1341-1349 ◽

Cited By ~ 8

Author(s):

Nicola Spotorno ◽

Julio Acosta-Cabronero ◽

Erik Stomrud ◽

Björn Lampinen ◽

Olof T Strandberg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Critical Role ◽

Disease Process ◽

Amyloid Β ◽

Cortical Atrophy ◽

Tau Pet ◽

Tau Aggregation ◽

The Relationship

Abstract A growing body of evidence suggests that the dysregulation of neuronal iron may play a critical role in Alzheimer’s disease. Recent MRI studies have established a relationship between iron accumulation and amyloid-β aggregation. The present study provides further insight demonstrating a relationship between iron and tau accumulation using magnetic resonance-based quantitative susceptibility mapping and tau-PET in n = 236 subjects with amyloid-β pathology (from the Swedish BioFINDER-2 study). Both voxel-wise and regional analyses showed a consistent association between differences in bulk magnetic susceptibility, which can be primarily ascribed to an increase in iron content, and tau-PET signal in regions known to be affected in Alzheimer’s disease. Subsequent analyses revealed that quantitative susceptibility specifically mediates the relationship between tau-PET and cortical atrophy measures, thus suggesting a modulatory effect of iron burden on the disease process. We also found evidence suggesting the relationship between quantitative susceptibility and tau-PET is stronger in younger participants (age ≤ 65). Together, these results provide in vivo evidence of an association between iron deposition and both tau aggregation and neurodegeneration, which help advance our understanding of the role of iron dysregulation in the Alzheimer’s disease aetiology.

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Lower MR-indexed locus coeruleus integrity in autosomal-dominant Alzheimer’s disease is related to cortical tau burden and memory deficits

10.1101/2020.11.16.20232561 ◽

2020 ◽

Author(s):

Martin J. Dahl ◽

Mara Mather ◽

Markus Werkle-Bergner ◽

Briana L. Kennedy ◽

Yuchuan Qiao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Resolution ◽

Locus Coeruleus ◽

Autosomal Dominant ◽

Brain Regions ◽

Cognitive Testing ◽

Autosomal Dominant Alzheimer’S Disease

AbstractAbnormally phosphorylated tau, an indicator of Alzheimer’s disease, begins to accumulate in the first decades of life in the locus coeruleus (LC), the primary source of cortical norepinephrine. Ensuing dysfunction in noradrenergic neuromodulation is hypothesized to contribute to Alzheimer’s progression. However, research into the role of the LC has been impeded by a lack of effective ways of assessing it in vivo. Advances in high-resolution brainstem magnetic resonance imaging (MRI) hold potential to investigate the association of locus coeruleus integrity and Alzheimer’s-related neuropathological markers in vivo.Leveraging a meta-analytical approach, we first synthesized LC localizations and dimensions across previously published studies to improve the reliability and validity of MR-based locus coeruleus detection. Next, we applied this refined volume of interest to determine whether MR-indexed LC integrity can serve as a marker for noradrenergic degeneration in early-onset Alzheimer’s disease. Eighteen participants (34.7±10.1 years; 9♀) with or known to be at-risk for mutations in genes associated with autosomal-dominant Alzheimer’s disease (ADAD) were investigated. Genotyping confirmed mutations in seven participants (PSEN1, n = 6; APP, n = 1), of which four were symptomatic. Participants underwent 3T-MRI, flortaucipir positron emission tomography (PET), and cognitive testing. LC MRI intensity, a non-invasive proxy for neuronal density, was semi-automatically extracted from high-resolution brainstem scans across the rostrocaudal extent of the nucleus.Relative to healthy controls, symptomatic participants showed lower LC intensity. This effect was pronounced in rostral segments of the nucleus that project to the mediotemporal lobe and other memory-relevant areas. Among carriers of ADAD-causing mutations, closer proximity to the mutation-specific median age of dementia diagnosis was associated with lower LC intensity. Leveraging a multivariate statistical approach, we revealed a pattern of LC-related tau pathology in occipito-temporo-parietal brain regions. Finally, higher locus intensity was closely linked to memory performance across a variety of neuropsychological tests.Our finding of diminished MR-indexed LC integrity in autosomal-dominant Alzheimer’s disease suggest a role of the noradrenergic system in this neurodegenerative disease.

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Performance of Plasma Amyloid β, Total Tau and Neurofilament Light Chain Levels for Alzheimer’s Disease Identification

10.21203/rs.3.rs-88939/v1 ◽

2020 ◽

Author(s):

Bin Jiao ◽

Hui Liu ◽

Lina Guo ◽

Xinxin Liao ◽

Yafang Zhou ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Light Chain ◽

Amyloid Β ◽

Amyloid Pet ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Plasma Biomarkers ◽

Total Tau ◽

T Tau

Abstract BackgroundRobust studies have focused on blood-based biomarkers for diagnosis of Alzheimer’s disease (AD), while the results were still controversary and failed verified in different cohorts. The aim of this study was to detect the levels of plasma amyloid β (Aβ), total tau (t-tau), and neurofilament light chain (NfL) in patients with AD and cognitive normal (CN) subjects, and clarify their associations with Aβ, t-tau, and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) as well as brain amyloid PET, and calculate the diagnostic efficiency of these characteristics regarding AD.Methods Plasma Aβ42, Aβ40, t-tau and NfL levels were detected by single-molecule array (Simoa) in 379 AD patients and 153 CN subjects. Additionally, lumbar puncture was conducted in 125 AD patients to detect Aβ42, Aβ40, t-tau, and p-tau levels. Brain amyloid PET was performed in 52 AD patients to identify brain amyloid deposition levels. Correlation analysis were performed between plasma biomarkers and typical biomarkers of AD, including CSF core biomarkers and amyloid PET burden. Finally, the diagnostic value of plasma biomarkers was further assessed by receiver operating characteristic (ROC) curve.ResultsCompared with the CN group, plasma Aβ42 and Aβ42/Aβ40 levels were significantly lower in AD patients, while Aβ40, t-tau and NfL levels were higher in AD patients. Among the AD patients, plasma Aβ42 was positively correlated with CSF Aβ42 (r = 0.195, p = 0.03) and Aβ42/Aβ40 (r = 0.208, p = 0.04). Moreover, plasma NfL was positively correlated with age, disease course and severity. The diagnostic model with combined plasma Aβ42, t-tau, and NfL levels controlled for age and APOE genotype showed the best performance to identify AD (area under the curve (AUC) = 0.88, sensitivity = 82.84%, specificity = 81.69%, cutoff value = 0.64).ConclusionsTrends revealed by core biomarkers were generally consistent in AD patients’ plasma and CSF. Combining plasma biomarkers can provide comparatively high AD diagnostic performance.

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The locus coeruleus: In‐vivo characterization with advanced MRI methods and associations with memory in older adults at risk for Alzheimer’s disease

Alzheimer s & Dementia ◽

10.1002/alz.045511 ◽

2020 ◽

Vol 16 (S4) ◽

Author(s):

Seraphina K. Solders ◽

Alexandra L. Clark ◽

Alexandra J. Weigand ◽

Scott F. Sorg ◽

Vitaly Galinsky ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

At Risk ◽

Locus Coeruleus ◽

In Vivo Characterization ◽

With Memory

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Procyanidins Extracted from Lotus Seedpod Ameliorate Amyloid-β-Induced Toxicity in Rat Pheochromocytoma Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4572893 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Hao Huang ◽

Peipei Yan ◽

Taoping Sun ◽

Xiaoxing Mo ◽

Jiawei Yin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pc12 Cells ◽

Senile Plaque ◽

Critical Role ◽

Amyloid Β ◽

Bdnf Signaling ◽

Lotus Seedpod

Alzheimer’s disease (AD) is a progressive neurodegenerative disease, which is characterized by extracellular senile plaque deposits, intracellular neurofibrillary tangles, and neuronal apoptosis. Amyloid-β (Aβ) plays a critical role in AD that may cause oxidative stress and downregulation of CREB/BDNF signaling. Anti-Aβ effect has been discussed as a potential therapeutic strategy for AD. This study aimed to identify the amelioration of procyanidins extracted from lotus seedpod (LSPC) on Aβ-induced damage with associated pathways for AD treatment. Rat pheochromocytoma (PC12) cells incubated with Aβ25–35 serve as an Aβ damage model to evaluate the effect of LSPC in vitro. Our findings illustrated that LSPC maintained the cellular morphology from deformation and reduced apoptosis rates of cells induced by Aβ25–35. The mechanisms of LSPC to protect cells from Aβ-induced damage were based on its regulation of oxidation index and activation of CREB/BDNF signaling, including brain-derived neurotrophic factor (BDNF) and phosphorylation of cAMP-responsive element-binding (CREB), protein kinase B (also known as AKT), and the extracellular signal-regulated kinase (ERK). Of note, by high-performance liquid chromatography-tandem mass spectroscopy (LC-MS/MS), several metabolites were detected to accumulate in vivo, part of which could take primary responsibility for the amelioration of Aβ-induced damage on PC12 cells. Taken together, our research elucidated the effect of LSPC on neuroprotection through anti-Aβ, indicating it as a potential pretreatment for Alzheimer’s disease.

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