Preserved blood-brain barrier and neurovascular coupling in female 5xFAD model of Alzheimer’s disease

Abstract

IntroductionDysfunction of the cerebral vasculature is considered one of the key components of Alzheimer’s disease (AD), but the mechanisms affecting individual brain vessels are poorly understood.MethodsHere, using in vivo two-photon microscopy in superficial cortical layers and ex vivo imaging across brain regions, we characterized blood–brain barrier (BBB) function and neurovascular coupling (NVC) at the level of individual brain vessels in adult female 5xFAD mice, an aggressive amyloid-β (Aβ) model of AD.ResultsWe report a lack of abnormal increase in adsorptive-mediated transcytosis of albumin and preserved paracellular barrier for fibrinogen and small molecules despite an extensive load of Aβ. Likewise, the NVC responses to somatosensory stimulation were preserved at all regulatory segments of the microvasculature: penetrating arterioles, precapillary sphincters, and capillaries. Lastly, the Aβ plaques did not affect the density of capillary pericytes.ConclusionOur findings provide direct evidence of preserved microvascular function in the 5xFAD mice and highlight the critical dependence of the experimental outcomes on the choice of preclinical models of AD. We propose that the presence of parenchymal Aβ does not warrant BBB and NVC dysfunction and that the generalized view that microvascular impairment is inherent to Aβ aggregation may need to be revised.

The cerebral blood flow response to neuroactivation is reduced in cognitively normal men with β-amyloid accumulation

“…Consequently, development of CAA accelerates cognitive decline. [49] A recent study on AD mice have demonstrated that parenchymal accumulation of Aβ do not affect the neurovascular coupling suggesting that the impairment of cerebrovascular function in brains with Aβ accumulation is from accumulations in vessel walls [50].…”

Cognitive decline, Aβ pathology, and blood–brain barrier function in aged 5xFAD mice

“…Recent vessel painting studies show that male 5xFAD mice show reduced vessel density associated with the middle cerebral artery regions and increased leakage hotspots from 4 to 12 months of age, but this was not observed in the case of female 5xFAD mice [ 50 ]. Studies by Zukhov et al and Giannoni et al show varying results on barrier integrity in female 5xFAD mice below and above 9 months of age, indicating that the effect of menopause cannot be completely excluded [ 21 , 51 ]. In this regard, the use of male 5xFAD mice excludes the effect of the estrous cycle in mice between 9 and 16 months of age.…”

“…More recently, a lack of difference in blood–brain barrier integrity between 7-and-10-month-old 5xFAD and age-matched WT mice was reported [ 51 ]. Specifically, no differences existed in vesicular transport of fluorescently labeled albumin across pial vessels, penetrating arterioles, and capillaries in 5xFAD and age-matched WT mice.…”

“…Our in vivo findings are consistent with these observations by using a different analytical approach. Zhukov et al [ 51 ] assessed barrier leakage by (1) averaging parenchymal intensities for 4–5 ROIs, and (2) excluded ROIs that were next to pial vessels and Aβ plaques. Based on this approach, the authors concluded that the blood–brain barrier is preserved in aged female 5xFAD mice.…”

Pericyte dysfunction is a key mediator of the risk of cerebral ischemia

“…gov/, 2022; Wafa et al, 2020). There has been a limited focus in research on the natural aging of pericytes and how age-related pericyte dysfunction impacts the cerebrovasculature, with conflicting reports regarding changes in pericyte density in aged experimental animals (Montagne et al, 2021;Zhukov et al, 2023). As the body ages, there is a chronic increase in pro-inflammatory markers and reactive oxygen (ROS) and nitrogen species (RNS) (Davalli et al, 2016).…”