Cerebrovascular Smooth Muscle Actin Is Increased in Nondemented Subjects With Frequent Senile Plaques at Autopsy: Implications for the Pathogenesis of Alzheimer Disease

Hulette, Christine M.; Ervin, John F.; Edmonds, Yvette; Antoine, Samantha; Stewart, Nicolas A.; Szymanski, Mari H.; Hayden, Kathleen M.; Pieper, Carl F.; Burke, James R.; Welsh‐Bohmer, Kathleen A.

doi:10.1097/nen.0b013e31819e6334

Cited by 5 publications

(4 citation statements)

References 33 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed a trend toward reduced SMA in leptomeningeal preparations from AD brains compared with control brains (Figure 3), although in keeping with reports of decreased SMA immunolabeling of cerebral blood vessels in AD (12,19,43) the reduction was not statistically significant in our samples. We did not observe any differences in SMA level according to CAA severity.…”

Section: Enrichment Of Sma and Nep In Leptomeningeal And Vessel-enricsupporting

confidence: 90%

“…Our finding of elevated SMA in leptomeninges and cerebral cortical vessel preparations compared with crude brain tissue homogenates demonstrates good retention and enrichment of small blood vessels. The SMA level in frontal and occipital leptomeninges from AD cases was lower than in controls, as observed by Hullete et al (19), but the difference in our samples did not reach significance. Hullete and colleagues reported that SMA immunolabeling was reduced in blood vessels showing accumulation of Aβ within the tunica media (12, 43).…”

Section: Discussionsupporting

confidence: 62%

See 1 more Smart Citation

Neprilysin Protects against Cerebral Amyloid Angiopathy and Aβ‐Induced Degeneration of Cerebrovascular Smooth Muscle Cells

Miners

Kehoe²,

Love³

2011

Brain Pathology

View full text Add to dashboard Cite

Neprilysin (NEP), which degrades amyloid-β (Aβ), is expressed by neurons and cerebrovascular smooth muscle cells (CVSMCs). NEP immunolabeling is reduced within cerebral blood vessels of Alzheimer's disease (AD) patients with cerebral amyloid angiopathy (CAA). We have now measured NEP enzyme activity in leptomeningeal and purified cerebral cortical blood vessel preparations from control and AD patients with and without CAA. Measurements were adjusted for smooth muscle actin (SMA) to control for variations in CVSMC content. NEP activity was reduced in CAA, in both controls and AD. In leptomeningeal vessels, NEP activity was related to APOE genotype, being highest in ε2-positive and lowest in ε4-positive brains. To assess the role of NEP in protecting CVSMCs from Aβ toxicity, we measured cell death in primary human adult CVSMCs exposed to Aβ(1-40) , Aβ(1-42) or Aβ(1-40(Dutch variant)) . Aβ(1-42) was most cytotoxic to CVSMCs. Aβ(1-42) -mediated cell death was increased following siRNA-mediated knockdown or thiorphan-mediated inhibition of NEP activity; conversely Aβ(1-42) -mediated cytotoxicity was reduced by the addition of somatostatin and NEP over-expression following transfection with NEP cDNA. Our findings suggest that NEP protects CVSMCs from Aβ toxicity and protects cerebral blood vessels from the development and complications of CAA.

show abstract

Section: Enrichment Of Sma and Nep In Leptomeningeal And Vessel-enricsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 62%

Neprilysin Protects against Cerebral Amyloid Angiopathy and Aβ‐Induced Degeneration of Cerebrovascular Smooth Muscle Cells

Miners

Kehoe²,

Love³

2011

Brain Pathology

View full text Add to dashboard Cite

show abstract

“…This severity of loss of αSMA in AD patients was highly dependent on the apolipoprotein E4 genotype [42]. However, the same group published some years ago that αSMA is increased in non-demented patients with frequent senile plaques [44]. While this seems to be conflicting results, there is now evidence that the progressing Aβ-associated angiopathy as well as the extent of cerebrovascular damage may play an essential role.…”

Section: Discussionmentioning

confidence: 99%

Alpha-Smooth Muscle Actin mRNA and Protein Are Increased in Isolated Brain Vessel Extracts of Alzheimer Mice

Hutter-Schmid

Humpel²

2016

Pharmacology

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain, characterized by extracellular beta-amyloid (Aβ) plaques, intracellular tau pathology, neurodegeneration and inflammation. There is clear evidence that the blood-brain barrier is damaged in AD and that vessel function is impaired. Alpha-smooth muscle actin (αSMA) is a prominent protein expressed on brain vessels, especially in cells located closer to the arteriole end of the capillaries, which possibly influences the blood vessel contraction. The aim of the present study was to observe αSMA protein and mRNA expression in isolated brain vessel extracts and cortex in an Alzheimer mouse model with strong Aβ plaque deposition. Our data revealed a prominent expression of αSMA protein in isolated brain vessel extracts of AD mice by Western blot analysis. Immunostaining showed that these vessels were associated with Aβ plaques. Quantitative real-time PCR analysis confirmed this increase at the mRNA expression level and showed a significant increase of transforming growth factor beta-1 mRNA expression in AD mice. In situ hybridization demonstrated a strong expression pattern of αSMA mRNA in the whole cortex and hippocampus. In conclusion, our data provide evidence that αSMA protein and mRNA are enhanced in vessels in an AD mouse model, possibly counteracting vessel malfunction in AD.

show abstract

“…Activity of smooth muscle actin (SMA) was reduced in the brains of patients with late stage AD, while increased arteriolar SMA expression together with frequent Aβ plaques observed in the brains of non-demented subjects suggests that increased SMA expression might represent a physiological response to neurodegeneration that could prevent or delay the onset of clinical dementia in subjects with cerebral AD neuropathology [ 67 ]. Vascular disease is thought by many authors to play a major role in the pathogenesis of AD and some even consider AD as being rather a primarily vascular than a neurodegenerative disorder [ 22 ],[ 68 ]-[ 74 ].…”

Section: Reviewmentioning

confidence: 99%

The overlap between vascular disease and Alzheimer’s disease - lessons from pathology

Attems

Jellinger

2014

BMC Med

565

420

View full text Add to dashboard Cite

Recent epidemiological and clinico-pathological data indicate considerable overlap between cerebrovascular disease (CVD) and Alzheimer’s disease (AD) and suggest additive or synergistic effects of both pathologies on cognitive decline. The most frequent vascular pathologies in the aging brain and in AD are cerebral amyloid angiopathy and small vessel disease. Up to 84% of aged subjects show morphological substrates of CVD in addition to AD pathology. AD brains with minor CVD, similar to pure vascular dementia, show subcortical vascular lesions in about two-thirds, while in mixed type dementia (AD plus vascular dementia), multiple larger infarcts are more frequent. Small infarcts in patients with full-blown AD have no impact on cognitive decline but are overwhelmed by the severity of Alzheimer pathology, while in early stages of AD, cerebrovascular lesions may influence and promote cognitive impairment, lowering the threshold for clinically overt dementia. Further studies are warranted to elucidate the many hitherto unanswered questions regarding the overlap between CVD and AD as well as the impact of both CVD and AD pathologies on the development and progression of dementia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-014-0206-2) contains supplementary material, which is available to authorized users.

show abstract

Cerebrovascular Smooth Muscle Actin Is Increased in Nondemented Subjects With Frequent Senile Plaques at Autopsy: Implications for the Pathogenesis of Alzheimer Disease

Cited by 5 publications

References 33 publications

Neprilysin Protects against Cerebral Amyloid Angiopathy and Aβ‐Induced Degeneration of Cerebrovascular Smooth Muscle Cells

Neprilysin Protects against Cerebral Amyloid Angiopathy and Aβ‐Induced Degeneration of Cerebrovascular Smooth Muscle Cells

Alpha-Smooth Muscle Actin mRNA and Protein Are Increased in Isolated Brain Vessel Extracts of Alzheimer Mice

The overlap between vascular disease and Alzheimer’s disease - lessons from pathology

Contact Info

Product

Resources

About