scholarly journals Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer’s disease

Brain ◽  
2021 ◽  
Author(s):  
Daniel Asby ◽  
Delphine Boche ◽  
Stuart Allan ◽  
Seth Love ◽  
J Scott Miners
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Growth Factor ◽  
Vascular Function ◽  
Temporal Cortex ◽  
Systemic Infection ◽  
Cerebral Hypoperfusion ◽  
Cerebrovascular Function ◽  
Tnf Α ◽  
Cytokine Levels

Abstract We studied the effects of systemic infection on brain cytokine level and cerebral vascular function in Alzheimer’s disease (AD) and vascular dementia (VaD), in superior temporal cortex (BA22) from AD (n = 75), VaD (n = 22) and age-matched controls (n = 46), stratified according to the presence or absence of terminal systemic infection. Brain cytokine levels were measured using Mesoscale Discovery Multiplex Assays and markers of cerebrovascular function were assessed by ELISA. Multiple brain cytokines were elevated in AD and VaD: Interleukin (IL)-15 and IL-17A were maximally elevated in end-stage Alzheimer’s disease (Braak tangle stage V-VI) whereas IL-2, IL-5, IL12p40 and IL-16 were highest in intermediate Braak tangle stage III-IV disease. Several cytokines (IL-1β, IL-6, TNF-α, IL-8 and IL-15) were further raised in AD with systemic infection. Cerebral hypoperfusion, indicated by decreased myelin-associated glycoprotein: Proteolipid protein-1 (MAG: PLP1) and increased vascular endothelial growth factor-A (VEGF), and blood-brain barrier leakiness, indicated by raised levels of fibrinogen, were exacerbated in AD and VaD, and also in non-dementia controls, with systemic infection. Aβ42 level did not vary with infection or in association with brain cytokine levels. In controls, cortical perfusion declined with increasing interferon-γ (IFN-γ), IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13 and tumour necrosis factor-α (TNF-α) but these relationships were lost with progression of AD, and with infection (even in BS 0-II brains). Cortical platelet-derived growth factor receptor-β (PDGFRβ), a pericyte marker, was reduced, and endothelin-1 (EDN1) level was increased in AD; these were related to Aβ level and disease progression and only modestly affected by systemic infection. Our findings indicate that systemic infection alters brain cytokine levels and exacerbates cerebral hypoperfusion and BBB leakiness associated with AD and VaD, independently of the level of insoluble Aβ. Our findings highlight systemic infection as an important contributor to dementia, requiring early identification and treatment in the elderly population.

Insulin-like growth factor-I (IGF-I) immunoreactivity in the Alzheimer's disease temporal cortex and hippocampus

1997 ◽  
Vol 49 (1-2) ◽  
pp. 283-290 ◽  
Author(s):  
B Connor ◽  
E.J Beilharz ◽  
C Williams ◽  
B Synek ◽  
P.D Gluckman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Growth Factor ◽  
Temporal Cortex ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

scholarly journals Losartan improves cerebrovascular function in a mouse model of Alzheimer's disease with combined overproduction of amyloid-β and transforming growth factor-β1

2016 ◽  
Vol 37 (6) ◽  
pp. 1959-1970 ◽  
Author(s):  
Panayiota Papadopoulos ◽  
Xin-Kang Tong ◽  
Hans Imboden ◽  
Edith Hamel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Growth Factor ◽  
Mouse Model ◽  
Cognitive Deficits ◽  
Transforming Growth Factor ◽  
Active Form ◽  
Transforming Growth Factor Β1 ◽  
Cerebrovascular Reactivity ◽  
Cerebrovascular Function

Alterations of the renin-angiotensin system have been implicated in the pathogenesis of Alzheimer's disease. We tested the efficacy of losartan (10 mg/kg/day for three months), a selective angiotensin II type 1 receptor antagonist, in alleviating cerebrovascular and cognitive deficits in double-transgenic mice (six months at endpoint) that overexpress a mutated form of the human amyloid precursor protein (APPSwe,Ind) and a constitutively active form of the transforming growth factor-β1, thereafter named A/T mice. Losartan rescued cerebrovascular reactivity, particularly the dilatory responses, but failed to attenuate astroglial activation and to normalize the neurovascular uncoupling response to sensory stimulation. The cognitive deficits of A/T mice were not restored by losartan nor were the increased brain levels of soluble and insoluble Aβ1–40 and Aβ1–42 peptides normalized. Our results are the first to demonstrate the capacity of losartan to improve cerebrovascular reactivity in an Alzheimer's disease mouse model of combined Aβ-induced vascular oxidative stress and transforming growth factor-β1-mediated vascular fibrosis. These data suggest that losartan may be promising for restoring cerebrovascular function in patients with vascular diseases at risk for vascular dementia or Alzheimer's disease. However, a combined therapy may be warranted for rescuing both vascular and cognitive deficits in a multifaceted pathology like Alzheimer's disease.

scholarly journals Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jonathan D. Cherry ◽  
Camille D. Esnault ◽  
Zachary H. Baucom ◽  
Yorghos Tripodis ◽  
Bertrand R. Huber ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chronic Traumatic Encephalopathy ◽  
Temporal Cortex ◽  
Head Impacts ◽  
Hippocampal Subfields ◽  
Mild Disease ◽  
Tau Isoforms ◽  
Ghost Tangles

AbstractChronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer’s disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.

scholarly journals Tumor necrosis factor α Inhibition for Alzheimer’s Disease

2017 ◽  
Vol 9 ◽  
pp. 117957351770927 ◽  
Author(s):  
Rudy Chang ◽  
Kei-Lwun Yee ◽  
Rachita K Sumbria
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Short Review ◽  
Tnf Α ◽  
Factor Α ◽  
Ad Therapy ◽  
Necrosis Factor

Tumor necrosis factor α (TNF-α) plays a central role in the pathophysiology of Alzheimer’s disease (AD). Food and Drug Administration–approved biologic TNF-α inhibitors are thus a potential treatment for AD, but they do not cross the blood-brain barrier. In this short review, we discuss the involvement of TNF-α in AD, challenges associated with the development of existing biologic TNF-α inhibitors for AD, and potential therapeutic strategies for targeting TNF-α for AD therapy.

scholarly journals Bayesian model reveals latent atrophy factors with dissociable cognitive trajectories in Alzheimer’s disease

2016 ◽  
Vol 113 (42) ◽  
pp. E6535-E6544 ◽  
Author(s):  
Xiuming Zhang ◽  
Elizabeth C. Mormino ◽  
Nanbo Sun ◽  
Reisa A. Sperling ◽  
Mert R. Sabuncu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Executive Function ◽  
Bayesian Model ◽  
Late Onset ◽  
Temporal Cortex ◽  
Cortical Atrophy ◽  
Future Research ◽  
Dementia Patients ◽  
With Memory

We used a data-driven Bayesian model to automatically identify distinct latent factors of overlapping atrophy patterns from voxelwise structural MRIs of late-onset Alzheimer’s disease (AD) dementia patients. Our approach estimated the extent to which multiple distinct atrophy patterns were expressed within each participant rather than assuming that each participant expressed a single atrophy factor. The model revealed a temporal atrophy factor (medial temporal cortex, hippocampus, and amygdala), a subcortical atrophy factor (striatum, thalamus, and cerebellum), and a cortical atrophy factor (frontal, parietal, lateral temporal, and lateral occipital cortices). To explore the influence of each factor in early AD, atrophy factor compositions were inferred in beta-amyloid–positive (Aβ+) mild cognitively impaired (MCI) and cognitively normal (CN) participants. All three factors were associated with memory decline across the entire clinical spectrum, whereas the cortical factor was associated with executive function decline in Aβ+ MCI participants and AD dementia patients. Direct comparison between factors revealed that the temporal factor showed the strongest association with memory, whereas the cortical factor showed the strongest association with executive function. The subcortical factor was associated with the slowest decline for both memory and executive function compared with temporal and cortical factors. These results suggest that distinct patterns of atrophy influence decline across different cognitive domains. Quantification of this heterogeneity may enable the computation of individual-level predictions relevant for disease monitoring and customized therapies. Factor compositions of participants and code used in this article are publicly available for future research.

scholarly journals Isovitexin modulates autophagy in Alzheimer’s disease via miR-107 signalling

2020 ◽  
Vol 11 (1) ◽  
pp. 391-401
Author(s):  
Jiang Cheng ◽  
Guowei Wang ◽  
Na Zhang ◽  
Fang Li ◽  
Lina Shi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Loss ◽  
The Elderly ◽  
Tnf Α ◽  
Autophagic Process ◽  
Molecular Signals ◽  
Ad Mouse Model ◽  
Mtor Signalling

AbstractBackground:Alzheimer’s disease (AD) is an ultimately fatal, degenerative brain disease in the elderly people. In the current work, we assessed the defensive capability of isovitexin (IVX) through an intracerebroventricular injection of streptozotocin (STZ)-induced AD mouse model.Methods:Mice were separated into four cohorts: sham-operated control mice; STZ-intoxicated Alzheimer’s mice; IVX cohort, IVX + STZ; and Ant-107 cohort, antagomiR-107 + IVX/STZ as in the IVX cohort.Results:The outcomes indicated that IVX administration ameliorated spatial memory loss and blunted a cascade of neuro-noxious episodes – including increased amyloid-beta (Aβ) and degraded myelin basic protein burden, neuroinflammation (represented by elevated caspase-1, TNF-α and IL-6 levels) and autophagic dysfunction (represented by altered LC3-II, Atg7 and beclin-1 expressions) – via the inhibition of PI3K/Akt/mTOR signalling axis. We considered the question of whether the epigenetic role of microRNA-107 (miR-107) has any impact on these events, by using antagomiR-107.Conclusion:This probing underscored that miR-107 could be a pivotal regulatory button in the activation of molecular signals linked with the beneficial autophagic process and anti-inflammatory activities in relation to IVX treatment. Hence, this report exemplifies that IVX could guard against Aβ toxicity and serve as an effectual treatment for patients afflicted with AD.

Relation between neuritic plaques and depressive state in Alzheimer's disease

2010 ◽  
Vol 22 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Gerben Meynen ◽  
Heleen Van Stralen ◽  
Jan H. Smit ◽  
Wouter Kamphorst ◽  
Dick F. Swaab ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Depressive Symptoms ◽  
Temporal Cortex ◽  
Clinical Severity ◽  
Depressive State ◽  
Neuritic Plaques ◽  
Prospective Longitudinal Study ◽  
Severity Of Dementia ◽  
Prospective Longitudinal

Meynen G, Van Stralen H, Smit JH, Kamphorst W, Swaab DF, Hoogendijk WJG. Relation between neuritic plaques and depressive state in Alzheimer's disease.Background:To investigate for the first time in a prospective study the relationship between depressive state and the neuropathological hallmarks of Alzheimer's disease, using a scale for depressive symptoms in dementia, while controlling for clinical severity of dementia.Method:Within the framework of a prospective longitudinal study of depression in Alzheimer's disease, patients with dementia underwent a clinical evaluation every six months during the last years of their lives, using the Cornell scale for depression in dementia to assess depressive symptoms and using the Functional Assessment Staging scale to control for clinical severity of dementia. The brains of 43 Alzheimer patients were obtained. The last clinical evaluations prior to death together with post-mortem neuropathology measures were analysed.Results:We found a correlation between the Cornell scores and the sum score for the density of neuritic plaques in the entire cortex (p = 0.027), and even stronger in the temporal cortex (p = 0.012). The observed correlations were independent of sex, age of death, clinical dementia severity and duration of Alzheimer's disease.Conclusions:This study shows a positive relationship between depressive state at time of death and the presence of neuritic plaques in Alzheimer's disease, which is independent of the clinical severity of dementia.

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