scholarly journals Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signalling to pericytes

2018 ◽  
Author(s):  
Ross Nortley ◽  
Anusha Mishra ◽  
Zane Jaunmuktane ◽  
Vasiliki Kyrargyri ◽  
Christian Madry ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cognitive Decline ◽  
Human Subjects ◽  
Amyloid Β ◽  
Vascular Compromise ◽  
Disease Relevance ◽  
Rat Cortical Slices ◽  
Aβ Generation

Vascular compromise occurs early in Alzheimer’s disease (AD) and other dementias1–3. Amyloid β (Aβ) reduces cerebral blood flow4–6 and, as most of the cerebral vasculature resistance is in capillaries7, Aβ might mainly act on contractile pericytes on capillary walls8–10. Employing human tissue to establish disease-relevance, and rodent experiments to define mechanism, we now show that Aβ constricts brain capillaries at pericyte locations in human subjects with cognitive decline. Applying soluble Aβ1-42 oligomers to live human cortical tissue constricted capillaries. Using rat cortical slices, this was shown to reflect Aβ evoking capillary pericyte contraction, with an EC50 of 4.7 nM, via the generation of reactive oxygen species and activation of endothelin ET-A receptors. In freshly-fixed diagnostic biopsies from human patients investigated for cognitive decline, mean capillary diameters were less in subjects showing Aβ deposition than in subjects without Aβ deposition. For patients with Aβ deposition, the capillary diameter was 31% less at pericyte somata than away from somata, predicting a halving of blood flow. Constriction of capillaries by Aβ will contribute to the energy lack1–3 occurring in AD, which promotes further Aβ generation11,12. This mechanism reconciles the amyloid hypothesis13–15 with the earliest events in AD being vascular1.

Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer's Disease Dementia

2018 ◽  
Vol 15 (4) ◽  
pp. 386-398 ◽  
Author(s):  
Fabricio Ferreira de Oliveira ◽  
Elizabeth Suchi Chen ◽  
Marilia Cardoso Smith ◽  
Paulo Henrique Ferreira Bertolucci
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Angiotensin Converting Enzyme ◽  
Cognitive Decline ◽  
Enzyme Inhibitors ◽  
Late Onset ◽  
Amyloid Β ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Alzheimer’S Disease Dementia

Background: While the angiotensin-converting enzyme degrades amyloid-β, angiotensinconverting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. Methods: Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. Results: For 193 patients, minor allele frequencies were 0.497 for rs1800764 – C (44.6% heterozygotes) and 0.345 for rs4291 – T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 – T and rs4291 – A, or for APOE4- carriers of rs1800764 – T or rs4291 – T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. Conclusion: ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.

scholarly journals 24(S)-Saringosterol Prevents Cognitive Decline in a Mouse Model for Alzheimer’s Disease

Marine Drugs ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 190
Author(s):  
Nikita Martens ◽  
Melissa Schepers ◽  
Na Zhan ◽  
Frank Leijten ◽  
Gardi Voortman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Cognitive Decline ◽  
Inflammatory Marker ◽  
Amyloid Β ◽  
Liver Fat ◽  
Gas Chromatography Mass Spectrometry ◽  
Memory Decline ◽  
Plaque Load

We recently found that dietary supplementation with the seaweed Sargassum fusiforme, containing the preferential LXRβ-agonist 24(S)-saringosterol, prevented memory decline and reduced amyloid-β (Aβ) deposition in an Alzheimer’s disease (AD) mouse model without inducing hepatic steatosis. Here, we examined the effects of 24(S)-saringosterol as a food additive on cognition and neuropathology in AD mice. Six-month-old male APPswePS1ΔE9 mice and wildtype C57BL/6J littermates received 24(S)-saringosterol (0.5 mg/25 g body weight/day) (APPswePS1ΔE9 n = 20; C57BL/6J n = 19) or vehicle (APPswePS1ΔE9 n = 17; C57BL/6J n = 19) for 10 weeks. Cognition was assessed using object recognition and object location tasks. Sterols were analyzed by gas chromatography/mass spectrometry, Aβ and inflammatory markers by immunohistochemistry, and gene expression by quantitative real-time PCR. Hepatic lipids were quantified after Oil-Red-O staining. Administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice without affecting the Aβ plaque load. Moreover, 24(S)-saringosterol prevented the increase in the inflammatory marker Iba1 in the cortex of APPswePS1ΔE9 mice (p < 0.001). Furthermore, 24(S)-saringosterol did not affect the expression of lipid metabolism-related LXR-response genes in the hippocampus nor the hepatic neutral lipid content. Thus, administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice independent of effects on Aβ load and without adverse effects on liver fat content. The anti-inflammatory effects of 24(S)-saringosterol may contribute to the prevention of cognitive decline.

scholarly journals Gestational Stress Augments Postpartum β-Amyloid Pathology and Cognitive Decline in a Mouse Model of Alzheimer’s Disease

2018 ◽  
Vol 29 (9) ◽  
pp. 3712-3724 ◽  
Author(s):  
Zahra Jafari ◽  
Jogender Mehla ◽  
Bryan E Kolb ◽  
Majid H Mohajerani
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Cognitive Decline ◽  
Noise Exposure ◽  
Amyloid Β ◽  
Control Group ◽  
Plaque Size ◽  
Model Of Alzheimer’S Disease ◽  
Gestational Stress

Abstract Besides well-known risk factors for Alzheimer’s disease (AD), stress, and in particular noise stress (NS), is a lifestyle risk factor common today. It is known that females are at a significantly greater risk of developing AD than males, and given that stress is a common adversity in females during pregnancy, we hypothesized that gestational noise exposure could exacerbate the postpartum development of the AD-like neuropathological changes during the life span. Pregnant APPNL-G-F/NL-G-F mice were randomly assigned to either the stress condition or control group. The stress group was exposed to the NS on gestational days 12–16, which resulted in a markedly higher hypothalamic–pituitary–adrenal (HPA) axis responsivity during the postpartum stage. Higher amyloid-β (Aβ) deposition and larger Aβ plaque size in the olfactory area were the early onset impacts of the gestational stress (GS) seen at the age of 4 months. This pattern of increased Aβ aggregation and larger plaque size were observed in various brain areas involved in both AD and stress regulation, especially in limbic structures, at the age of 6 months. The GS also produced anxiety-like behavior, deficits in learning and memory, and impaired motor coordination. The findings suggest that environmental stresses during pregnancy pose a potential risk factor in accelerating postpartum cognitive decline and AD-like neuropathological changes in the dams (mothers) later in life.

scholarly journals Neurophysiological signatures in Alzheimer’s disease are distinctly associated with TAU, amyloid-β accumulation, and cognitive decline

2020 ◽  
Vol 12 (534) ◽  
pp. eaaz4069 ◽  
Author(s):  
Kamalini G. Ranasinghe ◽  
Jungho Cha ◽  
Leonardo Iaccarino ◽  
Leighton B. Hinkley ◽  
Alexander J. Beagle ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Amyloid Β ◽  
Tracer Uptake ◽  
Therapeutic Approaches ◽  
Regional Patterns ◽  
Positron Emission ◽  
Network Synchrony ◽  
Network Disruptions

Neural synchrony is intricately balanced in the normal resting brain but becomes altered in Alzheimer’s disease (AD). To determine the neurophysiological manifestations associated with molecular biomarkers of AD neuropathology, in patients with AD, we used magnetoencephalographic imaging (MEGI) and positron emission tomography with amyloid-beta (Aβ) and TAU tracers. We found that alpha oscillations (8 to 12 Hz) were hyposynchronous in occipital and posterior temporoparietal cortices, whereas delta-theta oscillations (2 to 8 Hz) were hypersynchronous in frontal and anterior temporoparietal cortices, in patients with AD compared to age-matched controls. Regional patterns of alpha hyposynchrony were unique in each neurobehavioral phenotype of AD, whereas the regional patterns of delta-theta hypersynchrony were similar across the phenotypes. Alpha hyposynchrony strongly colocalized with TAU deposition and was modulated by the degree of TAU tracer uptake. In contrast, delta-theta hypersynchrony colocalized with both TAU and Aβ depositions and was modulated by both TAU and Aβ tracer uptake. Furthermore, alpha hyposynchrony but not delta-theta hypersynchrony was correlated with the degree of global cognitive dysfunction in patients with AD. The current study demonstrates frequency-specific neurophysiological signatures of AD pathophysiology and suggests that neurophysiological measures from MEGI are sensitive indices of network disruptions mediated by TAU and Aβ and associated cognitive decline. These findings facilitate the pursuit of novel therapeutic approaches toward normalizing network synchrony in AD.

The Impact of Amyloid-β or Tau on Cognitive Change in the Presence of Severe Cerebrovascular Disease

2020 ◽  
Vol 78 (2) ◽  
pp. 573-585
Author(s):  
Hyemin Jang ◽  
Hee Jin Kim ◽  
Yeong Sim Choe ◽  
Soo-Jong Kim ◽  
Seongbeom Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Interaction Effect ◽  
Significant Interaction ◽  
Amyloid Β ◽  
Cognitive Change ◽  
Significant Interaction Effect ◽  
The Impact

Background: As Alzheimer’s disease (AD) and cerebral small vessel disease (CSVD) commonly coexist, the interaction between two has been of the considerable interest. Objective: We determined whether the association of Aβ and tau with cognitive decline differs by the presence of significant CSVD. Methods: We included 60 subcortical vascular cognitive impairment (SVCI) from Samsung Medical Center and 82 Alzheimer’s disease-related cognitive impairment (ADCI) from ADNI, who underwent Aβ (florbetaben or florbetapir) and tau (flortaucipir, FTP) PET imaging. They were retrospectively assessed for 5.0±3.9 and 5.6±1.9 years with Clinical Dementia Rating-sum of boxes (CDR-SB)/Mini-Mental State Examination (MMSE). Mixed effects models were used to investigate the interaction between Aβ/tau and group on CDR-SB/MMSE changes. Results: The frequency of Aβ positivity (45% versus 54.9%, p = 0.556) and mean global FTP SUVR (1.17±0.21 versus 1.16±0.17, p = 0.702) were not different between the two groups. We found a significant interaction effect of Aβ positivity and SVCI group on CDR-SB increase/MMSE decrease (p = 0.013/p < 0.001), and a significant interaction effect of global FTP uptake and SVCI group on CDR-SB increase/MMSE decrease (p < 0.001 and p = 0.030). Finally, the interaction effects of regional tau and group were prominent in the Braak III/IV (p = 0.001) and V/VI (p = 0.003) not in Braak I/II region (p = 0.398). Conclusion: The association between Aβ/tau and cognitive decline is stronger in SVCI than in ADCI. Therefore, our findings suggested that Aβ positivity or tau burden (particularly in the Braak III/IV or V/VI regions) and CSVD might synergistically affect cognitive decline.

scholarly journals The Temporal Relationships between White Matter Hyperintensities, Neurodegeneration, Amyloid β, and Cognition

2020 ◽  
Author(s):  
Mahsa Dadar ◽  
Richard Camicioli ◽  
Simon Duchesne ◽  
D. Louis Collins ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Cognitive Decline ◽  
White Matter Hyperintensities ◽  
Amyloid Β ◽  
Disease Assessment ◽  
White Matter Hyperintensity ◽  
List Type ◽  
Temporal Relationships

ABSTRACTINTRODUCTIONCognitive decline in Alzheimer’s disease is associated with amyloid-β accumulation, neurodegeneration and cerebral small vessel disease, but the temporal relationships between these factors is not well established.METHODSData included white matter hyperintensity (WMH) load, grey matter (GM) atrophy and Alzheimer’s Disease Assessment Scale-Cognitive-Plus (ADAS13) scores for 720 participants and cerebrospinal fluid amyloid (Aβ1-42) for 461 participants from the Alzheimer’s Disease Neuroimaging Initiative. Linear regressions were used to assess the relationships between baseline WMH, GM, and Aβ1-42 to changes in WMH, GM, Aβ1-42, and cognition at one-year follow-up.RESULTSBaseline WMHs and Aβ1-42 predicted WMH increase and GM atrophy. Baseline WMHs, GM, and Aβ1-42 predicted worsening cognition. Only baseline Aβ1-42 predicted change in Aβ1-42.DISCUSSIONBaseline WMHs lead to greater future GM atrophy and cognitive decline, suggesting that WM damage precedes neurodegeneration and cognitive decline. Baseline Aβ1-42 predicted WMH increase, suggesting a potential role of amyloid in WM damage.Research in ContextSystematic Review: Both amyloid β and neurodegeneration are primary pathologies in Alzheimer’s disease. White matter hyperintensities (indicative of presence of cerebrovascular disease) might also be part of the pathological changes in Alzheimer’s. However, the temporal relationship between white matter hyperintensities, amyloid β, neurodegeneration, and cognitive decline is still unclear.Interpretation: Our results establish a potential temporal order between white matter hyperintensities, amyloid β, neurodegeneration, and cognitive decline, showing that white matter hyperintensities precede neurodegeneration and cognitive decline. The results provide some evidence that amyloid β deposition, in turn, precedes accumulation of white matter hyperintensities.Future Directions: The current findings reinforce the need for future longitudinal investigations of the mechanisms through which white matter hyperintensities impact the aging population in general and Alzheimer’s disease patients, in particular.

scholarly journals Automatic Prediction of Cognitive and Functional Decline Can Significantly Decrease the Number of Subjects Required for Clinical Trials in Early Alzheimer’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Neda Shafiee ◽  
Mahsa Dadar ◽  
Simon Ducharme ◽  
D. Louis Collins ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Decline ◽  
Functional Decline ◽  
Amyloid Β ◽  
Cognitive Test ◽  
Disease Heterogeneity ◽  
Early Alzheimer’S Disease

Background: While both cognitive and magnetic resonance imaging (MRI) data has been used to predict progression in Alzheimer’s disease, heterogeneity between patients makes it challenging to predict the rate of cognitive and functional decline for individual subjects. Objective: To investigate prognostic power of MRI-based biomarkers of medial temporal lobe atrophy and macroscopic tissue change to predict cognitive decline in individual patients in clinical trials of early Alzheimer’s disease. Methods: Data used in this study included 312 patients with mild cognitive impairment from the ADNI dataset with baseline MRI, cerebrospinal fluid amyloid-β, cognitive test scores, and a minimum of two-year follow-up information available. We built a prognostic model using baseline cognitive scores and MRI-based features to determine which subjects remain stable and which functionally decline over 2 and 3-year follow-up periods. Results: Combining both sets of features yields 77%accuracy (81%sensitivity and 75%specificity) to predict cognitive decline at 2 years (74%accuracy at 3 years with 75%sensitivity and 73%specificity). When used to select trial participants, this tool yields a 3.8-fold decrease in the required sample size for a 2-year study (2.8-fold decrease for a 3-year study) for a hypothesized 25%treatment effect to reduce cognitive decline. Conclusion: When used in clinical trials for cohort enrichment, this tool could accelerate development of new treatments by significantly increasing statistical power to detect differences in cognitive decline between arms. In addition, detection of future decline can help clinicians improve patient management strategies that will slow or delay symptom progression.

scholarly journals Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes

Science ◽  
2019 ◽  
Vol 365 (6450) ◽  
pp. eaav9518 ◽  
Author(s):  
Ross Nortley ◽  
Nils Korte ◽  
Pablo Izquierdo ◽  
Chanawee Hirunpattarasilp ◽  
Anusha Mishra ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Reactive Oxygen Species ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Oxygen Species ◽  
Brain Capillaries ◽  
Disease Relevance ◽  
The Brain ◽  
Capillary Walls

Cerebral blood flow is reduced early in the onset of Alzheimer’s disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. We used live and rapidly fixed biopsied human tissue to establish disease relevance, and rodent experiments to define mechanism. We found that in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aβ could potentially reduce energy lack and neurodegeneration in AD.

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