Brain and Circulating Levels of Aβ1–40 Differentially Contribute to Vasomotor Dysfunction in the Mouse Brain

Abstract

Background and Purpose Amyloid-β (Aβ), a peptide that accumulates in the brain and circulates in the blood of patients with Alzheimer’s disease (AD), alters the regulation of cerebral blood flow (CBF) and may contribute to the brain dysfunction underlying the dementia. However, the contributions of brain and circulating Aβ1–40 to the vascular dysfunction have not been elucidated. Methods we used transgenic mice overexpressing mutated forms of the amyloid precursor protein in which Aβ1–40 is elevated in blood and brain (Tg-2576) or only in brain (Tg-SwDI). Mice were equipped with a cranial widow and the increase in CBF induced by neural activity (whisker stimulation) or by topical application of endothelium-dependent vasodilators was assessed by laser-Doppler flowmetry. Results The cerebrovascular dysfunction was observed also in Tg-SwDI mice, but, despite ≈40% higher levels of brain Aβ1–40, the effect was less marked than in Tg-2576 mice. Intravascular administration of Aβ1–40 elevated plasma Aβ1–40 and enhanced the dysfunction in Tg-SwDI mice, but not in Tg-2576 mice. Conclusions The results provide evidence that Aβ1–40 acts on distinct luminal and abluminal vascular targets, the deleterious cerebrovascular effects of which are additive. Furthermore, the findings highlight the importance of circulating Aβ1–40 in the cerebrovascular dysfunction and may provide insight into the cerebrovascular alterations in conditions in which elevations in plasma Aβ1–40 occur.

Association of plasma β-amyloid with MRI markers of structural brain aging the 3-City Dijon study

“…The precise mechanisms underlying these associations remain unclear but amyloid production and accumulation are likely to be responsible for synaptic and neuronal degeneration and gray matter atrophy (Hardy and Selkoe, 2002). Animal studies have shown plasma Ab to be negatively correlated with density of neurons accumulating Ab deposits (Roy et al, 2014) and that elevations in both brain and circulating Ab levels can induce cerebrovascular dysfunction, with distinct and additive effects (Park et al, 2013). Cerebrovascular damage (e.g., brain hypoperfusion, hypoxia) may lead to neurodegenerative changes, or accumulation and reduced clearance of Ab from the brain, further amplifying neuronal injury and neurodegeneration (Bell et al, 2010;Deane et al, 2004).…”

Age-Dependent Neurovascular Dysfunction and Damage in a Mouse Model of Cerebral Amyloid Angiopathy

“…Experiments were performed in Tg-SwDI male mice at 3, 18, and 24 months on a C57BL/6 background. 11,14 Age-matched C57BL/6 male mice were used as wild-type (WT) controls.…”

“…Thus, the increase in cerebral blood flow (CBF) evoked by neural activity (functional hyperemia), a key mechanism that matches the metabolic needs of active neurons with the delivery of energy substrates via blood flow, and the ability of brain endothelial cells to control CBF are markedly impaired. 14 However, because previous studies were conducted in 3-month-old Tg-SwDI mice before amyloid deposition, the relationships linking vascular dysfunction, amyloid accumulation, and vascular damage have not been established. Furthermore, the mechanisms of the cerebrovascular dysfunction in Tg-SwDI mice remain to be defined.…”

Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family

“…27 These observations are consistent with findings published in other longitudinal studies, suggesting that plasma levels of Ab peptides increase in the preclinical phase of AD, successively declining with the progression of clinical dementia, reflecting the deposition of Ab peptides in the brain. [28][29][30][31][32][33] No substantial differences concerning clinical phenotype and course were evidenced comparing heterozygous and homozygous patients (table e-2). In these affected persons, homozygosity for the APP A713T mutation does not aggravate the clinical picture of the disease, which is in line with the classic definition of dominance.…”