Oligomeric Aβ in Alzheimer's Disease: Relationship to Plaque and Tangle Pathology, <i>APOE</i> Genotype and Cerebral Amyloid Angiopathy

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

doi:10.1111/j.1750-3639.2009.00321.x

Cited by 45 publications

(44 citation statements)

References 58 publications

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“…The activities in our A␤O preparations and in AD brain lysates reported here can be attributed to the prefibrillar oligomer according to the Glabe classification, because they were immunoneutralized by the conformation-specific antiserum A11 (8). In AD brains, prefibrillar oligomers and other forms of oligomers were found to accumulate focally as clusters of immunoreactive deposits (67)(68)(69). It is highly likely that focally A␤O can reach the low nanomolar concentrations required for activating microglia in the course of AD development when A␤O progressively accumulates (3).…”

Section: Discussionmentioning

confidence: 87%

Amyloid-β Protein Oligomer at Low Nanomolar Concentrations Activates Microglia and Induces Microglial Neurotoxicity

Maezawa

Zimin²,

Wulff³

et al. 2011

Journal of Biological Chemistry

243

218

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Neuroinflammation and associated neuronal dysfunction mediated by activated microglia play an important role in the pathogenesis of Alzheimer disease (AD). Microglia are activated by aggregated forms of amyloid-␤ protein (A␤), usually demonstrated in vitro by stimulating microglia with micromolar concentrations of fibrillar A␤, a major component of amyloid plaques in AD brains. Here we report that amyloid-␤ oligomer (A␤O), at 5-50 nM, induces a unique pattern of microglia activation that requires the activity of the scavenger receptor A and the Ca 2؉ -activated potassium channel KCa3.1. A␤O treatment induced an activated morphological and biochemical profile of microglia, including activation of p38 MAPK and nuclear factor B. Interestingly, although increasing nitric oxide (NO) production, A␤O did not increase several proinflammatory mediators commonly induced by lipopolyliposacharides or fibrillar A␤, suggesting that A␤O stimulates both common and divergent pathways of microglia activation. A␤O at low nanomolar concentrations, although not neurotoxic, induced indirect, microglia-mediated damage to neurons in dissociated cultures and in organotypic hippocampal slices. The indirect neurotoxicity was prevented by (i) doxycycline, an inhibitor of microglia activation; (ii) TRAM-34, a selective KCa3.1 blocker; and (iii) two inhibitors of inducible NO synthase, indicating that KCa3.1 activity and excessive NO release are required for A␤O-induced microglial neurotoxicity. Our results suggest that A␤O, generally considered a neurotoxin, may more potently cause neuronal damage indirectly by activating microglia in AD.A␤, 2 a hydrophobic protein derived from proteolytic processing of the amyloid-␤ precursor protein, self-aggregates into amyloid fibrils and deposits as amyloid plaques, one of the pathological hallmarks of AD. A␤ aggregates, especially those of the 42-residue A␤42, are potent toxins to neurons. In addition, A␤ aggregates activate microglia, which clear A␤, but in the process release inflammatory mediators that cause indirect neurotoxicity (1). A commonly held view is that microglia react to fA␤ deposited in amyloid plaques, which form a nidus for microglia-mediated neuronal damage. However, because the number of amyloid plaques correlates poorly with the degree of dementia (2, 3), it follows that plaque-associated microglia may not be a major player in cognitive impairment. Emerging evidence including two recent in vivo positron emission tomography studies indicates that microglia may respond to stimuli other than plaque fA␤ (4, 5), suggesting that alternative ways to activate microglia must occur in AD.In addition to fibrillar forms, A␤ exists in various smaller assemblies in AD brains, which may mediate diverse toxic effects at different stages of the disease. Although these smaller aggregates, variously named as oligomers (A␤O), protofibrils, amyloid pores, or AD diffusible ligands, have been considered transient or metastable intermediates in fibril formation (6), some of them may not be obligate inter...

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Section: Discussionmentioning

confidence: 87%

Amyloid-β Protein Oligomer at Low Nanomolar Concentrations Activates Microglia and Induces Microglial Neurotoxicity

Maezawa

Zimin²,

Wulff³

et al. 2011

Journal of Biological Chemistry

243

218

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“…The use of an in vivo method, the dynamic PiB PET scan, would potentially establish the role of the fibrillar amyloid in the primary prevention trials [68]. The key role of the fibrillar oligomers in AD disease is also confirmed by the biochemical data obtained from brain homogenates [69], where significant correlations were found between the levels of fibrillar oligomers and cognitive decline as well as the neuropathological hallmarks of AD [70]. It has been previously reported that 89% of the brain vessels from the apoE4 transgenic mice that showed evidence of hemorrhage contained fibrillar amyloid deposits, based on Thioflavine-S staining and confirmed by electron microscopy [71].…”

Section: Structural Changes On the Cortical Capillariesmentioning

confidence: 81%

A Hyperlipidemic Diet Induces Structural Changes in Cerebral Blood Vessels

Constantinescu¹,

Safciuc²,

Sima³

2011

CNR

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The cerebrovascular pathology is an important contributor to the death rate presently. Hyperlipidemia , an established risk factor for cardiovascular diseases, is also incriminated in the neurodegenerative disorders. The aim of this study was to evaluate the effect of a hyperlipidemic (HL) diet on the morphology of the cerebral vessels and on the amyloid deposition in the HL hamster, an accepted model of atherosclerosis. Hamsters fed a HL diet were tested periodically for serum parameters and sacrificed after 3 and 6 months. The methods used were: paraffin embedding, thioflavin S amyloid staining, fluorescence and electron microscopy (EM). Increased serum cholesterol and triglycerides characterized the HL hamsters. The carotid arteries developed fatty streaks after 3 months and atherosclerotic plaques after 6 months HL diet. The brain cortex comprised irregularly shaped microvessels with large perivascular spaces, enlarged endothelial cells (EC) and occasionally a lumen full of lipoprotein particles. The thioflavin S reaction revealed a discreet staining of the capillaries walls; the EC cytoplasm and basal lamina contained a fibrillar material, with a pattern similar to an incipient amyloid deposit. Some large meningeal vessels from animals with serum cholesterol over 1000 mg/dl presented an intense autofluorescence in the adventitia; EM examination identified lipid-loaded perivascular cells in these areas. In conclusion, the detected morphological changes induced by the HL diet could represent a serious impairment for the normal brain function. These data may contribute to the better understanding of the risks of hyperlipidemia for the mental health, and its reversal could become a new therapeutic approach for neurodegenerative disorders.

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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

Self Cite

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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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Oligomeric Aβ in Alzheimer's Disease: Relationship to Plaque and Tangle Pathology, APOE Genotype and Cerebral Amyloid Angiopathy

Cited by 45 publications

References 58 publications

Amyloid-β Protein Oligomer at Low Nanomolar Concentrations Activates Microglia and Induces Microglial Neurotoxicity

Amyloid-β Protein Oligomer at Low Nanomolar Concentrations Activates Microglia and Induces Microglial Neurotoxicity

A Hyperlipidemic Diet Induces Structural Changes in Cerebral Blood Vessels

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

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