Higher Soluble Amyloid β Concentration in Frontal Cortex of Young Adults than in Normal Elderly or Alzheimer's Disease

Helmond, Zoë Van; Miners, Scott; Kehoe, Patrick Gavin; Love, Seth

doi:10.1111/j.1750-3639.2010.00374.x

Cited by 39 publications

(50 citation statements)

References 41 publications

(61 reference statements)

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“…Aβ production gradually shifts from soluble to insoluble Aβ peptides with increasing age [34], which may shorten the time from occurrence of pathological amyloid metabolism to onset of clinical symptoms. A third reason could be that Aβ is a less important cause of dementia in the oldest old.…”

Section: Discussionmentioning

confidence: 99%

Amyloid β42 and Total Tau Levels in Cerebrospinal Fluid Associate with Survival in an 85-Year-Old Population-Based Cohort Followed until Death

Ribbe

Kern

Hansson

et al. 2019

Dement Geriatr Cogn Disord

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Background: Dementia of Alzheimer’s type (AD) is related to decreased survival. It is not clear whether also biological markers of AD are related to mortality. Low levels of amyloid beta-42 (Aβ42) and high levels of total tau (T-tau) protein in cerebrospinal fluid (CSF) are established biomarkers for AD. Objective: Our aim was to investigate whether levels of Aβ42 and T-tau are associated with survival among octogenarians independently of dementia status. Methods: Sixty-five 85-year-olds underwent lumbar puncture and were followed with repeated neuropsychiatric examinations until death. Results: Lower CSF Aβ42 (p = 0.010) and higher CSF T-tau (p = 0.005) at the age of 85 were associated with lower survival independently of dementia status at baseline and follow-up. Low CSF Aβ42 and high CSF T-tau were also related to baseline dementia at the age of 85 years, and lower CSF Aβ42 with increased dementia incidence during the first 3 years of follow-up. Conclusions: Biological markers of AD are associated with mortality in octogenarians. The reason for this needs further study. Our findings highlight the importance to consider the competing risk of death when evaluating biological markers of AD in the very old.

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Section: Discussionmentioning

confidence: 99%

Amyloid β42 and Total Tau Levels in Cerebrospinal Fluid Associate with Survival in an 85-Year-Old Population-Based Cohort Followed until Death

Ribbe

Kern

Hansson

et al. 2019

Dement Geriatr Cogn Disord

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“…Recently it was reported that the level of soluble oligomeric Aβ in frontal cortex of young adults is higher than that of elderly people or Alzheimer’ disease patients using ELISA experiments (Halmond et al, 2010); potentially calling into question a relationship between oligomeric Aβ (as measured by the ELISA) with Alzheimer disease pathogenesis. In this study we observed that the level of HMW Aβ from TBS-soluble fraction is under-estimated in ELISA experiments due to a possible masking effect either by itself or interacting molecules, and the treatment with 8 M Guanidine-HCl increases the measured concentration of Aβ in HMW Aβ fractions using our specific ELISA conditions (Figure 2A).…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid β Peptide

et al. 2012

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Alzheimer’s disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid β peptide (Aβ) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component. The apolipoprotein E epsilon 4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However it is still unknown how apoE impacts the process of Aβ oligomerization. Here, we found that the level of Aβ oligomers in APOEε4/ε4 AD patient brains is 2.7 times higher than those in APOEε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aβ oligomers. To test this hypothesis, we examined apoE’s effect on Aβ oligomer formation. Using both synthetic Aβ and a split-luciferase method for monitoring Aβ oligomers, we observed that apoE increased the level of Aβ oligomers in an isoform dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE carboxy-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Aβ oligomers. Taken together, these data show that lipidated apoE, especially apoE4, increases Aβ oligomers in the brain. Higher levels of Aβ oligomers in the brains of APOEε4/ε4 carriers compared to APOEε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD.

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“…We prepared soluble and insoluble (guanidine‐extractable) fractions of the homogenates for Aβ measurement as reported in previous studies 1, 5, 32, 55, 56, 57, 58.…”

Section: Methodsmentioning

confidence: 99%

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

2015

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The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post‐mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin‐1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin‐associated glycoprotein:proteolipid protein‐1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III–IV). Although MAG:PLP1 remained low in advanced AD (stage V–VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin‐converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin‐converting enzyme‐2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42‐mediated upregulation of ECE2, is a contributor.

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Higher Soluble Amyloid β Concentration in Frontal Cortex of Young Adults than in Normal Elderly or Alzheimer's Disease

Cited by 39 publications

References 41 publications

Amyloid β42 and Total Tau Levels in Cerebrospinal Fluid Associate with Survival in an 85-Year-Old Population-Based Cohort Followed until Death

Amyloid β42 and Total Tau Levels in Cerebrospinal Fluid Associate with Survival in an 85-Year-Old Population-Based Cohort Followed until Death

Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid β Peptide

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

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