scholarly journals Widespread Reduced Density of Noradrenergic Locus Coeruleus Axons in the App Knock-In Mouse Model of Amyloid-β Amyloidosis

2021 ◽  
pp. 1-18
Author(s):  
Yasufumi Sakakibara ◽  
Yu Hirota ◽  
Kyoko Ibaraki ◽  
Kimi Takei ◽  
Sachie Chikamatsu ◽  
...  
Keyword(s):  
Locus Coeruleus ◽  
Somatostatin Receptor ◽  
Amyloid Β ◽  
Immunohistochemical Method ◽  
Noradrenergic Neurons ◽  
Tau Pathology ◽  
Age Related ◽  
Neurotrophin 3 ◽  
Underlying Mechanisms ◽  
Reduced Density

Background: The locus coeruleus (LC), a brainstem nucleus comprising noradrenergic neurons, is one of the earliest regions affected by Alzheimer’s disease (AD). Amyloid-β (Aβ) pathology in the cortex in AD is thought to exacerbate the age-related loss of LC neurons, which may lead to cortical tau pathology. However, mechanisms underlying LC neurodegeneration remain elusive. Objective: Here, we aimed to examine how noradrenergic neurons are affected by cortical Aβ pathology in AppNL-G-F/NL-G-F knock-in mice. Methods: The density of noradrenergic axons in LC-innervated regions and the LC neuron number were analyzed by an immunohistochemical method. To explore the potential mechanisms for LC degeneration, we also examined the occurrence of tau pathology in LC neurons, the association of reactive gliosis with LC neurons, and impaired trophic support in the brains of AppNL-G-F/NL-G-F mice. Results: We observed a significant reduction in the density of noradrenergic axons from the LC in aged App NL-G-F/NL-G-F mice without neuron loss or tau pathology, which was not limited to areas near Aβ plaques. However, none of the factors known to be related to the maintenance of LC neurons (i.e., somatostatin/somatostatin receptor 2, brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) were significantly reduced in App NL-G-F/NL-G-F mice. Conclusion: This study demonstrates that cortical Aβ pathology induces noradrenergic neurodegeneration, and further elucidation of the underlying mechanisms will reveal effective therapeutics to halt AD progression.

scholarly journals The Norepinephrine Metabolite DOPEGAL Confers Locus Coeruleus Tau Vulnerability and Propagation via Asparagine Endopeptidase

2019 ◽  
Author(s):  
Seong Su Kang ◽  
Xia Liu ◽  
Eun Hee Ahn ◽  
Jie Xiang ◽  
Fredric P. Manfredsson ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Locus Coeruleus ◽  
Selective Vulnerability ◽  
Monoamine Oxidase A ◽  
Noradrenergic Neurons ◽  
Tau Pathology ◽  
Intact Cells ◽  
Tau Aggregation ◽  
The Brain

AbstractAberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer’s disease (AD)-like neuropathology in the human brain; however, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here we show that 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), which is produced exclusively in noradrenergic neurons by monoamine oxidase A (MAO-A) metabolism of norepinephrine (NE), activates asparagine endopeptidase (AEP) that cleaves Tau at residue N368 into aggregation- and propagation-prone forms, thereby leading to LC degeneration and the spread of Tau pathology. DOPEGAL triggers AEP-cleaved Tau aggregationin vitroand in intact cells, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal a novel molecular mechanism underlying the selective vulnerability of LC neurons in AD.

scholarly journals Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy

2020 ◽  
Author(s):  
Jamie M Walker ◽  
Timothy E Richardson ◽  
Kurt Farrell ◽  
Megan A Iida ◽  
Chan Foong ◽  
...  
Keyword(s):  
Medial Temporal Lobe ◽  
Regional Distribution ◽  
Amyloid Β ◽  
Staging System ◽  
Selective Vulnerability ◽  
Neurofibrillary Degeneration ◽  
Braak Stage ◽  
Tau Pathology ◽  
Semiquantitative Assessment ◽  
Age Related

Abstract Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

Age-related decline in the activity of noradrenergic neurons of the rat locus coeruleus

1982 ◽  
Vol 251 (1) ◽  
pp. 174-176 ◽  
Author(s):  
Hans-Rudolf Olpe ◽  
Martin W. Steinmann
Keyword(s):  
Locus Coeruleus ◽  
Noradrenergic Neurons ◽  
Age Related

scholarly journals Lack of Cannabinoid Receptor Type-1 Leads to Enhanced Age-Related Neuronal Loss in the Locus Coeruleus

2020 ◽  
Vol 22 (1) ◽  
pp. 5
Author(s):  
Alessandra Gargano ◽  
Eva Beins ◽  
Andreas Zimmer ◽  
Andras Bilkei-Gorzo
Keyword(s):  
Locus Coeruleus ◽  
Cannabinoid Receptor ◽  
Receptor Type ◽  
Minor Role ◽  
Noradrenergic Neurons ◽  
Wild Type ◽  
Cannabinoid Receptor Type 1 ◽  
Age Related ◽  
Brain Ageing

Our laboratory and others have previously shown that cannabinoid receptor type-1 (CB1r) activity is neuroprotective and a modulator of brain ageing; a genetic disruption of CB1r signaling accelerates brain ageing, whereas the pharmacological stimulation of CB1r activity had the opposite effect. In this study, we have investigated if the lack of CB1r affects noradrenergic neurons in the locus coeruleus (LC), which are vulnerable to age-related changes; their numbers are reduced in patients with neurodegenerative diseases and probably also in healthy aged individuals. Thus, we compared LC neuronal numbers between cannabinoid 1 receptor knockout (Cnr1−/−) mice and their wild-type littermates. Our results reveal that old Cnr1−/− mice have less noradrenergic neurons compared to their age-matched wild-type controls. This result was also confirmed by the analysis of the density of noradrenergic terminals which proved that Cnr1−/− mice had less compared to the wild-type controls. Additionally, we assessed pro-inflammatory glial activity in the LC. Although the density of microglia in Cnr1−/− mice was enhanced, they did not show enhanced inflammatory profile. We hypothesize that CB1r activity is necessary for the protection of noradrenergic neurons, but its anti-inflammatory effect probably only plays a minor role in it.

Tau Pathologies Mediate the Associations of Vascular Risk Burden with Cognitive Impairments in Non-demented Elders: The CABLE Study

2021 ◽  
pp. 1-8
Author(s):  
G.-X. Yu ◽  
Y.-N. Ou ◽  
Y.-L. Bi ◽  
Y.-H. Ma ◽  
H. Hu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Vascular Dysfunction ◽  
Cognitive Impairments ◽  
Amyloid Β ◽  
Vascular Risk ◽  
Tau Pathology ◽  
Mediation Analyses ◽  
Large Cohort Study ◽  
Underlying Mechanisms ◽  
T Tau

BACKGROUND: Studies suggested that vascular dysfunction might increase the risk of developing Alzheimer’s disease (AD), but the underlying mechanisms still remain obscure. Objective: To evaluate the associations of vascular risk burden with AD core pathologies and investigate the effects of AD core pathologies on relationships between vascular risk burden and cognitive impairments. Design: The Chinese Alzheimer’s Biomarker and LifestyLE (CABLE) study was principally focusing on aging, as well as the risk factors and biomarkers of AD initiated in 2017. Setting: The CABLE study was a large cohort study established in Qingdao, China. Participants: A total of 618 non-demented elders were obtained from CABLE study. Measurements: The general vascular risk burden was assessed by the Framingham General Cardiovascular Risk Score (FGCRS). Multivariate linear regression analyses were performed to evaluate the associations of FGCRS with cerebrospinal fluid (CSF) AD biomarkers and cognition. Casual mediation analyses were performed to investigate the mediating effects of AD biomarkers on cognition. Results: Increased FGCRS was related to higher levels of CSF total tau (t-tau, p < 0.001), phosphorylated tau (p-tau, p < 0.001) as well as the ratio of t-tau and amyloid-β 42 (t-tau/Aβ42, p = 0.010), and lower Chinese-Modified Mini-Mental State Examination (CM-MMSE, p = 0.010) score. Stratified analysis indicated that age modified the associations, with FGCRS being significantly associated with tau pathology (p < 0.001 for t-tau and p-tau) in middle-aged group (<65 years old), instead of older group. The influences of FGCRS on cognitive impairments were partially mediated by tau pathologies (a maximum proportion of 20.9%). Conclusions: Tau pathology might be a pivotal mediator for effects of vascular risk on cognitive decline. Early and comprehensive intervention for vascular risk factors might be a potential approach to delaying or preventing cognitive impairment and AD.

scholarly journals Reduced density of noradrenergic fibers without prominent neuron loss or tau pathology in the locus coeruleus in APP knock‐in mouse models of Aβ amyloidosis

2020 ◽  
Vol 16 (S2) ◽  
Author(s):  
Koichi M. Iijima ◽  
Yasufumi Sakakibara ◽  
Kyoko Ibaraki ◽  
Kimi Takei ◽  
Takashi Saito ◽  
...  
Keyword(s):  
Locus Coeruleus ◽  
Mouse Models ◽  
Tau Pathology ◽  
Neuron Loss ◽  
Noradrenergic Fibers ◽  
Reduced Density

scholarly journals The Role of Eicosanoids in Alzheimer’s Disease

2019 ◽  
Vol 16 (14) ◽  
pp. 2560 ◽  
Author(s):  
Roger G. Biringer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Biological Functions ◽  
Tau Pathology ◽  
Cellular Processes ◽  
Eicosanoid Metabolism ◽  
Underlying Mechanisms

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders known. Estimates from the Alzheimer’s Association suggest that there are currently 5.8 million Americans living with the disease and that this will rise to 14 million by 2050. Research over the decades has revealed that AD pathology is complex and involves a number of cellular processes. In addition to the well-studied amyloid-β and tau pathology, oxidative damage to lipids and inflammation are also intimately involved. One aspect all these processes share is eicosanoid signaling. Eicosanoids are derived from polyunsaturated fatty acids by enzymatic or non-enzymatic means and serve as short-lived autocrine or paracrine agents. Some of these eicosanoids serve to exacerbate AD pathology while others serve to remediate AD pathology. A thorough understanding of eicosanoid signaling is paramount for understanding the underlying mechanisms and developing potential treatments for AD. In this review, eicosanoid metabolism is examined in terms of in vivo production, sites of production, receptor signaling, non-AD biological functions, and known participation in AD pathology.

scholarly journals Gram-negative bacteria and their lipopolysaccharides in Alzheimer’s disease: pathologic roles and therapeutic implications

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Hyeon soo Kim ◽  
Sujin Kim ◽  
Soo Jung Shin ◽  
Yong Ho Park ◽  
Yunkwon Nam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Targets ◽  
Amyloid Β ◽  
Gram Negative Bacteria ◽  
Therapeutic Approaches ◽  
Tau Pathology ◽  
Gram Negative ◽  
Therapeutic Implications ◽  
Age Related

AbstractAlzheimer’s disease (AD) is the most serious age-related neurodegenerative disease and causes destructive and irreversible cognitive decline. Failures in the development of therapeutics targeting amyloid-β (Aβ) and tau, principal proteins inducing pathology in AD, suggest a paradigm shift towards the development of new therapeutic targets. The gram-negative bacteria and lipopolysaccharides (LPS) are attractive new targets for AD treatment. Surprisingly, an altered distribution of gram-negative bacteria and their LPS has been reported in AD patients. Moreover, gram-negative bacteria and their LPS have been shown to affect a variety of AD-related pathologies, such as Aβ homeostasis, tau pathology, neuroinflammation, and neurodegeneration. Moreover, therapeutic approaches targeting gram-negative bacteria or gram-negative bacterial molecules have significantly alleviated AD-related pathology and cognitive dysfunction. Despite multiple evidence showing that the gram-negative bacteria and their LPS play a crucial role in AD pathogenesis, the pathogenic mechanisms of gram-negative bacteria and their LPS have not been clarified. Here, we summarize the roles and pathomechanisms of gram-negative bacteria and LPS in AD. Furthermore, we discuss the possibility of using gram-negative bacteria and gram-negative bacterial molecules as novel therapeutic targets and new pathological characteristics for AD.

Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy

2019 ◽  
Vol 16 (8) ◽  
pp. 710-722 ◽  
Author(s):  
Xiao-Ying Sun ◽  
Quan-Xiu Dong ◽  
Jie Zhu ◽  
Xun Sun ◽  
Li-Fan Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Synaptic Proteins ◽  
Morris Water Maze Test ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Maze Test ◽  
N2a Cells ◽  
Tau Aggregation

Background: Alzheimer’s Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown. Method: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. Results: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. Conclusion: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

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