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LC cell loss in aMCI. a Representative TH-ir neuron and fiber staining in dorsal pontine tissue harvested from NCI, aMCI, and mild/moderate AD subjects. b Unbiased stereological cell counts revealed a significant ~30% decrease in the number of LC neurons in aMCI compared to NCI cases. There was a ~50% loss of LC neurons in the AD group compared to NCI. **, p < 0.01, ***, p < 0.001 compared to NCI, via one-way ANOVA with Bonferroni post hoc testing. There was also a significant ~25% difference in neuronal cell counts between the aMCI and AD groups (p < 0.05). me5 = mesencephalic tract of 5. Scale Bar = 100 μm
Source publication
A major feature of Alzheimer’s disease (AD) is the loss of noradrenergic locus coeruleus (LC) projection neurons that mediate attention, memory, and arousal. However, the extent to which the LC projection system degenerates during the initial stages of AD is still under investigation. To address this question, we performed tyrosine hydroxylase (TH)...
Contexts in source publication
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... incubated over- night with rabbit TH antiserum (1:500; Millipore, Billerica, MA). The sections were then sequentially incubated with biotinylated goat anti-rabbit IgG and avidin-biotin com- plex (ABC; Vector Labs, Burlingame, CA) and developed using 3,3′-diaminobenzidine (DAB) enhanced with nickel II sulfate to yield a blue-black reaction product (Fig. ...
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... immunohistochemistry was used to estimate changes in the number of noradrenergic LC neurons across the clinical diagnostic groups (Fig. 1). Qualita- tively, we observed a step-wise decrement in TH-ir neu- rons within the LC from NCI to aMCI to mild/moderate AD (Fig. 1a). Unbiased stereological cell counts validated these observations. The estimated number of TH-ir LC neurons in the NCI group was 19,495 ± 2,891(mean ± SD; range = 25,867-14,758), whereas neuron number was ...
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... immunohistochemistry was used to estimate changes in the number of noradrenergic LC neurons across the clinical diagnostic groups (Fig. 1). Qualita- tively, we observed a step-wise decrement in TH-ir neu- rons within the LC from NCI to aMCI to mild/moderate AD (Fig. 1a). Unbiased stereological cell counts validated these observations. The estimated number of TH-ir LC neurons in the NCI group was 19,495 ± 2,891(mean ± SD; range = 25,867-14,758), whereas neuron number was progressively decreased in the aMCI (14,283 ± 2,757; range = 19,874-10,645) and AD ( 10,628 ± 2,946; range = 15,834-6,453) groups. ...
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... group was 19,495 ± 2,891(mean ± SD; range = 25,867-14,758), whereas neuron number was progressively decreased in the aMCI (14,283 ± 2,757; range = 19,874-10,645) and AD ( 10,628 ± 2,946; range = 15,834-6,453) groups. Statistical comparisons revealed a significant ~30% decrease in the number of LC neu- rons in aMCI compared to NCI cases (p < 0.01) (Fig. 1b). An additional ~25% decrease in LC neuron number was quantified in AD compared to aMCI (p < 0.05), resulting in a ~45-50% loss of LC neurons in the AD group com- pared to NCI (p < 0.001) (Fig. 1b). Total LC neuron number was similar between males and females in each diagnostic group (data not ...
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... groups. Statistical comparisons revealed a significant ~30% decrease in the number of LC neu- rons in aMCI compared to NCI cases (p < 0.01) (Fig. 1b). An additional ~25% decrease in LC neuron number was quantified in AD compared to aMCI (p < 0.05), resulting in a ~45-50% loss of LC neurons in the AD group com- pared to NCI (p < 0.001) (Fig. 1b). Total LC neuron number was similar between males and females in each diagnostic group (data not ...
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... transcripts encoding other functional classes of genes relevant to AD pathogenesis were unaffected. For example, levels of amyloid-β precursor protein (App) and several genes related to APP metabolism, such as beta-site APP-cleaving enzyme 1 (Bace1), presenilin 1 (Psen1), and APP family member genes amyloid precursor-like protein 1 (Aplp1) and amyloid precursor-like protein 2 (Aplp2) were not differentially regulated in LC neurons across the clinical groups (Additional file 1: Figure S1). ...
Citations
... In accord with this idea, it was recently shown 565 that sleep fragmentation occurring as a result of "natural aging" was caused by hyperexcitability 566 of the orexin-LH neurons (Li et al., 2022). The LC is one of the first brain regions to exhibit Tau 567 pathology in human AD patients or even seemingly healthy younger adults, and also shows 568 early-stage pathology in PS19 mice (Braak et al., 2011;Kelly et al., 2017;Zhu et al., 2018) (Fig. 569 7). This suggests that LC may be one of the first brain regions affected in Tauopathies We began our study by asking when sleep disruption and Tau pathology occur in PS19 mice in 610 an age and sex-dependent manner. ...
Sleep disruption and impaired synaptic processes are common features in neurodegenerative diseases, including Alzheimer's disease (AD). Hyperphosphorylated Tau is known to accumulate at neuronal synapses in AD, contributing to synapse dysfunction. However, it remains unclear how sleep disruption and synapse pathology interact to contribute to cognitive decline. Here, we examined sex-specific onset and consequences of sleep loss in AD/tauopathy model PS19 mice. Using a piezoelectric home-cage monitoring system, we showed PS19 mice exhibited early-onset and progressive hyperarousal, a selective dark-phase sleep disruption, apparent at 3 months in females and 6 months in males. Using the Morris water maze test, we report that chronic sleep disruption (CSD) accelerated the onset of decline of hippocampal spatial memory in PS19 males only. Hyperarousal occurs well in advance of robust forebrain synaptic Tau burden that becomes apparent at 6–9 months. To determine whether a causal link exists between sleep disruption and synaptic Tau hyperphosphorylation, we examined the correlation between sleep behavior and synaptic Tau, or exposed mice to acute or chronic sleep disruption at 6 months. While we confirm that sleep disruption is a driver of Tau hyperphosphorylation in neurons of the locus ceruleus, we were unable to show any causal link between sleep loss and Tau burden in forebrain synapses. Despite the finding that hyperarousal appears earlier in females, female cognition was resilient to the effects of sleep disruption. We conclude sleep disruption interacts with the synaptic Tau burden to accelerate the onset of cognitive decline with greater vulnerability in males.
... A similar trend was observed in the plasma concentrations of norepinephrine, which were significantly lower in control subjects and patients with advanced AD than in patients with early-stage AD (Pillet et al., 2020). Meanwhile, neuronal loss and shrinkage of the locus coeruleus (the primary site of noradrenaline synthesis) occur during AD progression (Takahashi et al., 2015;Kelly et al., 2017). We hypothesized that differences in the plasma levels of norepinephrine may be related to blood-brain barrier breakdown and locus coeruleus shrinkage, which weakens the central control of the sympathetic system. ...
Background
Previous studies have shown that Alzheimer’s disease (AD) can cause myocardial damage. However, whether there is a causal association between AD and non-ischemic cardiomyopathy (NICM) remains unclear. Using a comprehensive two-sample Mendelian randomization (MR) method, we aimed to determine whether AD and family history of AD (FHAD) affect left ventricular (LV) structure and function and lead to NICM, including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM).
Methods
The summary statistics for exposures [AD, paternal history of AD (PH-AD), and maternal history of AD (MH-AD)] and outcomes (NICM, HCM, DCM, and LV traits) were obtained from the large European genome-wide association studies. The causal effects were estimated using inverse variance weighted, MR-Egger, and weighted median methods. Sensitivity analyses were conducted, including Cochran’s Q test, MR-Egger intercept test, MR pleiotropy residual sum and outlier, MR Steiger test, leave-one-out analysis, and the funnel plot.
Results
Genetically predicted AD was associated with a lower risk of NICM [odds ratio (OR) 0.9306, 95% confidence interval (CI) 0.8825–0.9813, p = 0.0078], DCM (OR 0.8666, 95% CI 0.7752–0.9689, p = 0.0119), and LV remodeling index (OR 0.9969, 95% CI 0.9940–0.9998, p = 0.0337). Moreover, genetically predicted PH-AD was associated with a decreased risk of NICM (OR 0.8924, 95% CI 0.8332–0.9557, p = 0.0011). MH-AD was also strongly associated with a decreased risk of NICM (OR 0.8958, 95% CI 0.8449–0.9498, p = 0.0002). Different methods of sensitivity analysis demonstrated the robustness of the results.
Conclusion
Our study revealed that AD and FHAD were associated with a decreased risk of NICM, providing a new genetic perspective on the pathogenesis of NICM.
... Hippocampi of 11 male athletes who participated in American football with a history of repetitive mild TBI were provided to an author (EJM) by Boston University School of Medicine [13,14] (see Table 1). The human CTE cases (n = 11 with a mean age of 84.3) were diagnosed as stage-IV, the most severe category, according to the neuropathological McKee and colleagues' criteria for this disorder [15]. ...
Epidemiological studies have unveiled a robust link between exposure to repetitive mild traumatic brain injury (r-mTBI) and elevated susceptibility to develop neurodegenerative disorders, notably chronic traumatic encephalopathy (CTE). The pathogenic lesion in CTE cases is characterized by the accumulation of hyperphosphorylated tau in neurons around small cerebral blood vessels which can be accompanied by astrocytes that contain phosphorylated tau, the latter termed tau astrogliopathy. However, the contribution of tau astrogliopathy to the pathobiology and functional consequences of r-mTBI/CTE or whether it is merely a consequence of aging remains unclear. We addressed these pivotal questions by utilizing a mouse model harboring tau-bearing astrocytes, GFAPP301L mice, subjected to our r-mTBI paradigm. Despite the fact that r-mTBI did not exacerbate tau astrogliopathy or general tauopathy, it increased phosphorylated tau in the area underneath the impact site. Additionally, gene ontology analysis of tau-bearing astrocytes following r-mTBI revealed profound alterations in key biological processes including immunological and mitochondrial bioenergetics. Moreover, gene array analysis of microdissected astrocytes accrued from stage IV CTE human brains revealed an immunosuppressed astroglial phenotype similar to tau-bearing astrocytes in the GFAPP301L model. Additionally, hippocampal reduction of proteins involved in water transport (AQP4) and glutamate homeostasis (GLT1) was found in the mouse model of tau astrogliopathy. Collectively, these findings reveal the importance of understanding tau astrogliopathy and its role in astroglial pathobiology under normal circumstances and following r-mTBI. The identified mechanisms using this GFAPP301L model may suggest targets for therapeutic interventions in r-mTBI pathogenesis in the context of CTE.
... The NBM is a major cholinergic hub targeting limbic and cortical areas, and is involved in cortical activation, attention, executive functions, and memory processes [5,6]. Autopsy studies have revealed the degeneration of LC neurons in prodromal AD, associated with disease severity [7][8][9]. They also mention a reduction in cortical choline-acetyl transferase activity [10] related to neuronal loss in the basal forebrain, mainly in the Ch4 neuronal group constituting the NBM, in the early and predementia stages of the disease [11][12][13][14]. ...
Background
The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer’s disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls.
Methods
Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy.
Results
We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients.
Conclusions
The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.
... In AD, in the early stages on preclinical stages of the disease, when cognitive impairments are moderate or absent, progressive accumulation of NFTs and subsequent reduction in the number of neurons occurs in the LC [16]. Moreover, the rate of decline in cognitive functions, such as episodic memory, working memory, and processing speed, is associated with the degree of reduction in the number of LC neurons and the density of NFTs [48,50]. ...
... The reduction in the number of LC neurons correlates with the severity of AD and life expectancy, while the morphology of the neurons also changes: the size of the soma of the neurons, the number of dendrites, and the volume of the nuclei change [16,51,52]. According to research, the number of LC neurons decreases by approximately 30% as the disease progresses from the absence of cognitive symptoms to mild symptoms and by 25% when transitioning from mild to moderate AD [47,50]. Neurons in the rostral part of the LC, projecting to cortical structures and the hippocampus, are more susceptible to degeneration [47,53]. ...
Locus coeruleus is a small bilateral nucleus in the brainstem. It is the main source of norepinephrine (noradrenaline) throughout the central nervous system (about 70% of all norepinephrine in the central nervous system), and, as shown in numerous studies, it is involved in regulating a significant number of functions. The detailed study of the functions of the Locus Coeruleus (LC) and its significance in human life became possible only after the development of histofluorescence methods for monoamines in the 1960s. The widespread locus coeruleus-norepinephrine (LC-NE) projection system regulates the entire central nervous system and modulates sensory processing, motor behavior, arousal, and cognitive processes. Damage to the LC and the associated decrease in norepinephrine levels are involved in a wide range of clinical conditions and pathological processes. Although much about the anatomy and physiology of the LC is currently known, its ultimate role in the regulation of behavior, control of the sleep-wake cycle, stress response, and the development of pathological conditions (such as Alzheimer's disease, dementia, depression, suicidal behavior, chronic traumatic encephalopathy, and Parkinson's disease) is not fully understood. Non-invasive visualization of the LC can be used for differential diagnosis, determining the stage of the disease, and predicting its course. Studying the dysfunction of the LC-norepinephrine system, involved in the pathogenesis of various neurological diseases, may ultimately form the basis for the development of new treatment methods based on the pharmacological elevation of norepinephrine levels. In this review, we will attempt to highlight the key points regarding the structure and function of the Locus Coeruleus, as well as outline the main directions and prospects for its study.
... It would be valuable for future studies to examine the links between premorbid IQ and other socio-behavioral proxies of cognitive reserve in older adults [39]. Finally, studies examining neuronal density in the LC have reported wide variability possibly related to the methodology, sample size, disease stages and whether only TH-positive or neuromelanin bearing neurons were included [44][45][46][47][48][49][50][51]. While very labor-intense, a comprehensive, unbiased stereological evaluation is required to better understand the evolution of LC neuronal count as a function of tangle accumulation and disease progression. ...
The locus coeruleus-noradrenaline system regulates brain-wide neural activity involved in cognition and behavior. Integrity of this subcortical neuromodulatory system is proposed to be a substrate of cognitive reserve that may be strengthened by lifetime cognitive and social activity. Conversely, accumulation of tau tangles in the brainstem locus coeruleus nuclei is recently studied as a very early marker of Alzheimer’s disease (AD) pathogenesis and cognitive vulnerability, even among older adults without cognitive impairment or significant cerebral AD pathologies. This clinical-pathologic study examined whether locus coeruleus tangle density was cross-sectionally associated with lower antemortem cognitive performance and social activity among 142 cognitively unimpaired and impaired older adults and whether social activity, a putative reserve factor, mediated the association of tangle density and cognition. We found that greater locus coeruleus tangle density was associated with lower social activity for the whole sample and in the cognitively unimpaired group alone and these associations were independent of age, sex, education, depressive symptoms, and burden of cerebral amyloid and tau. The association of locus coeruleus tangle density with lower cognitive performance was partially mediated by level of social activity. These findings implicate the locus coeruleus-noradrenaline system in late-life social function and support that locus coeruleus tangle pathology is associated with lower levels of social activity, independent of cerebral AD pathologies, and specifically among older adults who are cognitively unimpaired. Early brainstem pathology may impact social function, and level of social function, in turn, influences cognition, prior to canonical stages of AD.
... and Dementia (27). In Alzheimer's Disease, high expression of the Tau protein has been observed in LC (45)(46), as well as a neural decrease of 15 to 55%, and abnormal NA content in the LC affecting memory, perception, and visuospatial ability (47); while in Parkinson's disease and dementia there is a neuronal decrease of LC (27) followed by microgliosis and disruption in the biosynthesis of NA (48). ...
Living Donor Liver Transplantation (LDLT) is a promising approach to treating end-stage liver diseases, however, some post-operatory complications such as pneumonia, bacteremia, urinary tract infections, and hepatic dysfunction have been reported. In murine models using partial hepatectomy (PHx), a model that emulates LDLT, it has been determined that the synthesis of hepatic cell proliferation factors that are associated with noradrenaline synthesis are produced in locus coeruleus (LC). In addition, studies have shown that PHx decreases GABA and 5-HT2A receptors, promotes loss of dendritic spines, and favors microgliosis in rat hippocampus. The GABA and serotonin-altered circuits suggest that catecholaminergic neurons such as dopamine and noradrenaline neurons, which are highly susceptible to cellular stress, can also be damaged. To understand post-transplant affections and to perform well-controlled studies it is necessary to know the potential causes that explain as a liver surgical procedure can produce brain damage. In this paper, we review several cellular processes that could induce gliosis in LC after rat PHx.
... Images is creating by Biorender. (Kelly et al., 2017). Age also decreases the action of the canine cholinergic system. ...
In treating brain diseases, such as canine cognitive dysfunction, most currently available potent drugs have weak therapeutic efficacy. One of the causes is the inability of the substance to reach the brain in therapeutic quantities. These pharmaceuticals lacked targeted mechanisms for drug delivery, coming about in an elevated drugs concentration in imperative organs, which driven to drug harmfulness. In recent years, cell-free treatment (conditioned medium) determined from animal and human stem cells have provided new promise for treating brain diseases, as CM can stimulate the regeneration of neurons and prevent the inflammation and apoptotic of neurons caused by pathology or aging. On the other hand, it is well known that Chitosan-Hydrogel (CH) is a polymer derived from natural sources. It has been authorized for use in biomedical use because of its uncommon biodegradability, biocompatibility, and mucoadhesive properties. CH modification has been utilized to generate nanoparticles (NPs) for intranasal and intravenous brain targeting. NPs shown upgraded drug take-up to the brain with decreased side impacts due to their drawn out contact time with the nasal mucosa, surface charge, nano size, and capacity to extend the tight intersections inside the mucosa. Due to the aforementioned distinctive characteristics, developing CHNPs load with Bovine Umbilical Mesenchymal Stem Cell Conditioned Medium is crucial as a new therapeutic strategy for canine cognitive dysfunction.
... Given that the cause of loss of function is the loss of neurones it is worth 10 considering the possibility that the underlying neurone loss both spreads and 11 accelerates, i.e., possess classic features of an infection-like mechanism. 12 Theoretical neuroscience often turns to the mathematics of infection to describe these 13 clinical phenomena. In particular the mathematical form known as the logistic 2 (Fig.1). ...
... 56 Therefore, if brain function was directly linked with neurone number a steady lifelong 57 decrease of function would be predicted. In contrast with expectation, there are threshold effects 11,12,13 in brain function. 61 The brain has the capacity to adapt to functional change associated with loss of 62 neurones. ...
The conventional interpretation ¹ of a logistic curve in biology is that it indicates the presence of an infection-like mechanism bounded by a saturation limit e.g. saturation occurs when the whole population has been infected. However, a logistic form may be generated by the fluctuating approach of biological systems to, and then exceeding, an effect threshold.
The commonly observed trends in frequency and degree of cognitive loss in neurodegenerative disease (NDD) are consistent with a threshold-crossing model. Whereas direct evidence of real life NDD being driven by an infection-like mechanism remains elusive 2,3 .
Variation in susceptibility to NDD may be explained by variation in the rate of biological ageing (e.g. neurodegeneration rate, or, metabolic interference), height of threshold and initial reserve. Each is potentially modifiable and clinically informative.
... Cerebral amyloid angiopathy (CAA) that involves small arteries, as well as arterioles in grey and white matter, occurs frequently during the progression of AD, and it contributes to vascular pathologies and white matter rarefaction (WMr). Depigmentation and loss of noradrenergic locus coeruleus projection neurons are commonly observed in the early stages of AD [15] and appear to be associated with increased cortical Aβ plaque and NFT loads [16]. Therefore, a second aim of the study was to investigate potential relationships between cortical diffusivity measures and non-cortical neuropathologic features, such as locus coeruleus hypopigmentation (LCh), CAA, WMr, and atherosclerosis of the circle of Willis (ACW). ...
Background:
There has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology. This study aimed to characterise the associations between the main Alzheimer's disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated.
Methods:
Forty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD+, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC-the "ABC score" from NIA-AA recommendations). Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated. Finally, the effect of coexistent pathologies-Lewy body disease and TAR DNA-binding protein 43 (TDP-43)-on cortical microstructure was assessed.
Results:
Cortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD+ in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD+. LCh was associated with PerpPD+, ParlPD, and MD. Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology.
Conclusions:
Cortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain. Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making. Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy.
