Differential Changes in Phosphorylation of Tau at PHF-1 and 12E8 Epitopes During Brain Ischemia and Reperfusion in Gerbils

Gordon‐Krajcer, Wanda; Koźniewska, Ewa; Łazarewicz, Jerzy W.; Księżak-Reding, Hanna

doi:10.1007/s11064-006-9199-3

Cited by 40 publications

(33 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…31 For example, reduced cerebral blood flow in animal models leads to accumulation of amyloid-b oligomers, and increases both neuronal amyloid-b levels and neuronal tau phosphorylation. [32][33][34] Observational studies in humans also suggest an association between CVD risk factors and AD clinical diagnosis, as well as neuropathologic changes of AD. 35 Further supporting the view that ischemia may lead to NFTs in old age, we found that those with high levels of atherosclerosis had more NFTs.…”

Section: Resultsmentioning

confidence: 99%

Neuropathologic basis of white matter hyperintensity accumulation with advanced age

et al. 2013

View full text Add to dashboard Cite

Objective: To determine which vascular pathology measure most strongly correlates with white matter hyperintensity (WMH) accumulation over time, and whether Alzheimer disease (AD) neuropathology correlates with WMH accumulation.Methods: Sixty-six older persons longitudinally followed as part of an aging study were included for having an autopsy and .1 MRI scan, with last MRI scan within 36 months of death. Mixed-effects models were used to examine the associations between longitudinal WMH accumulation and the following neuropathologic measures: myelin pallor, arteriolosclerosis, microvascular disease, microinfarcts, lacunar infarcts, large-vessel infarcts, atherosclerosis, neurofibrillary tangle rating, and neuritic plaque score. Each measure was included one at a time in the model, adjusted for duration of follow-up and age at death. A final model included measures showing an association with p , 0.1.Results: Mean age at death was 94.5 years (5.5 SD). In the final mixed-effects models, arteriolosclerosis, myelin pallor, and Braak score remained significantly associated with increased WMH accumulation over time. In post hoc analysis, we found that those with Braak score 5 or 6 were more likely to also have high atherosclerosis present compared with those with Braak score 1 or 2 (p 5 0.003).Conclusion: Accumulating white matter changes in advanced age are likely driven by small-vessel ischemic disease. Additionally, these results suggest a link between AD pathology and white matter integrity disruption. This may be due to wallerian degeneration secondary to neurodegenerative changes. Alternatively, a shared mechanism, for example ischemia, may lead to both vascular brain injury and neurodegenerative changes of AD. The observed correlation between atherosclerosis and AD pathology supports the latter. Disruption of white matter integrity, frequently observed as white matter hyperintensities (WMH) on T2-weighted MRI sequences, has detrimental effects on cognitive function, motor performance, and functional status in the elderly [1][2][3] and is associated with increased risk of all types of dementia, including Alzheimer disease (AD).4 Furthermore, WMH accumulation over time has been shown to increase risk of cognitive decline. 3,[5][6][7] While the general consensus is that the etiology of white matter accumulation is secondary to small-vessel ischemic changes, [8][9][10][11][12][13] it is not well established whether those with faster WMH accumulation may have contributions from other pathologies. Because accumulation of WMH increases risk of cognitive decline, identifying the pathologic correlates of faster WMH accumulation could potentially guide interventions targeting specific risks for prevention and treatment to preserve cognitive function in the elderly. Furthermore, while there are previous observations supporting a link between cerebrovascular disease (CVD) and AD, 14 it is not clearly established whether WMH progression is associated with neurodegenerative changes of AD. Thus, our aim was to bette...

show abstract

Section: Resultsmentioning

confidence: 99%

Neuropathologic basis of white matter hyperintensity accumulation with advanced age

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Moreover, in AD mice, mild hypoperfusion increases neuronal Ab levels and tau phosphophorylation at an epitotope associated with AD-type paired helical filaments (Koike et al 2010). Brain ischemia in rodents leads to accumulation of hyperphosphorylated tau in neurons and filament formation similar to that present in human AD tauopathy (Gordon-Krajcer et al 2007). Arterial carotid occlusion in rats leads to memory impairment, neuronal dysfunction, synaptic changes and accumulation of neurotoxic Ab oligomers (Wang et al 2010).…”

Section: Cerebral Blood Flow Dysregulation and Reductionsmentioning

confidence: 91%

Neurovascular Dysfunction and Faulty Amyloid -Peptide Clearance in Alzheimer Disease

Sagare

Bell

Zloković

2012

Cold Spring Harbor Perspectives in Medicine

215

177

View full text Add to dashboard Cite

Neurovascular dysfunction is an integral part of Alzheimer disease (AD). Changes in the brain vascular system may contribute in a significant way to the onset and progression of cognitive decline and the development of a chronic neurodegenerative process associated with accumulation of amyloid b-peptide (Ab) in brain and cerebral vessels in AD individuals and AD animal models. Here, we review the role of the neurovascular unit and molecular mechanisms in cerebral vascular cells behind the pathogenesis of AD. In particular, we focus on blood-brain barrier (BBB) dysfunction, decreased cerebral blood flow, and impaired vascular clearance of Ab from brain. The data reviewed here support an essential role of the neurovascular and BBB mechanisms in AD pathogenesis.

show abstract

“…In fact, it was reported that mild hypoperfusion increased neuronal Aβ concentration and the levels of phosphorylated tau in an AD mouse model [76]. It was also observed that brain ischemia in rodent leads to increased levels of hyperphosphorylated tau in neurons and filaments similar to those observed in human AD tauopathy [148]. Moreover, arterial carotid occlusion in rats resulted in neuronal dysfunction, including synaptic changes [149].…”

Section: Reduction Of Capillary Density and Cerebral Blood Flow In Agingmentioning

confidence: 91%

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

2015

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline that afflicts as many as 45 % of individuals who survive past the age of 85. AD has been associated with neurovascular dysfunction and brain accumulation of amyloid-β peptide, as well as tau phosphorylation and neurodegeneration, but the pathogenesis of the disease is still somewhat unclear. According to the amyloid cascade hypothesis of AD, accumulation of amyloid-β peptide (Aβ) aggregates initiates a sequence of events leading to neuronal injury and loss, and dementia. Alternatively, the vascular hypothesis of AD incorporates the vascular contribution to the disease, stating that a primary insult to brain microcirculation (e.g., stroke) not only contributes to amyloidopathy but initiates a non-amyloidogenic pathway of vascular-mediated neuronal dysfunction and injury, which involves blood-brain barrier compromise, with increased permeability of blood vessels, leakage of blood-borne components into the brain, and, consequently, neurotoxicity. Vascular dysfunction also includes a diminished brain capillary flow, causing multiple focal ischemic or hypoxic microinjuries, diminished amyloid-β clearance, and formation of neurotoxic oligomers, which lead to neuronal dysfunction. Here we present and discuss relevant findings on the contribution of vascular alterations during aging to AD, with the hope that a better understanding of the players in the "orchestra" of neurodegeneration will be useful in developing therapies to modulate the "symphony".

show abstract

Differential Changes in Phosphorylation of Tau at PHF-1 and 12E8 Epitopes During Brain Ischemia and Reperfusion in Gerbils

Cited by 40 publications

References 50 publications

Neuropathologic basis of white matter hyperintensity accumulation with advanced age

Neuropathologic basis of white matter hyperintensity accumulation with advanced age

Neurovascular Dysfunction and Faulty Amyloid -Peptide Clearance in Alzheimer Disease

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

Contact Info

Product

Resources

About