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Denser brain capillary network with preserved pericytes in Alzheimer's disease.

ABSTRACT: Pericytes are vascular mural cells that surround capillaries of the central nervous system (CNS). They are crucial for brain development and contribute to CNS homeostasis by regulating blood-brain barrier function and cerebral blood flow. It has been suggested that pericytes are lost in Alzheimer's disease (AD), implicating this cell type in disease pathology. Here, we have employed state-of-the-art stereological morphometry techniques as well as tissue clearing and two-photon imaging to assess the distribution of pericytes in two independent cohorts of AD (n = 16 and 13) and non-demented controls (n = 16 and 4). Stereological quantification revealed increased capillary density with a normal pericyte population in the frontal cortex of AD brains, a region with early amyloid β deposition. Two-photon analysis of cleared frontal cortex tissue confirmed the preservation of pericytes in AD cases. These results suggest that pericyte demise is not a general hallmark of AD pathology.

SUBMITTER: Fernandez-Klett F

PROVIDER: S-EPMC8018033 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Denser brain capillary network with preserved pericytes in Alzheimer's disease.

Fernandez-Klett Francisco F Brandt Lasse L Fernández-Zapata Camila C Abuelnor Basim B Middeldorp Jinte J Sluijs Jacqueline A JA Curtis Maurice M Faull Richard R Harris Laura W LW Bahn Sabine S Hol Elly M EM Priller Josef J

Brain pathology (Zurich, Switzerland) 20200929 6

Pericytes are vascular mural cells that surround capillaries of the central nervous system (CNS). They are crucial for brain development and contribute to CNS homeostasis by regulating blood-brain barrier function and cerebral blood flow. It has been suggested that pericytes are lost in Alzheimer's disease (AD), implicating this cell type in disease pathology. Here, we have employed state-of-the-art stereological morphometry techniques as well as tissue clearing and two-photon imaging to assess ...[more]

PMID: 32876357

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Project description:Cerebral pericytes are an integral component of the neurovascular unit, which governs the blood-brain barrier. There is paucity of knowledge on cortical pericytes across different dementias. We quantified cortical pericytes in capillaries in 124 post-mortem brains from subjects with post-stroke dementia (PSD), vascular dementia (VaD), Alzheimer's disease (AD) and AD-VaD (Mixed) and, post-stroke non-demented (PSND) stroke survivors as well as normal ageing controls. Collagen 4 (COL4)-positive nucleated pericyte soma were identified as protrusions on capillaries of the frontal cortex. The COL4-positive somata or nodule-like cell bodies were also verified by platelet derived growth factor receptor-β (PDGFR-β) immunohistochemistry. The mean (± SEM) pericyte somata in frontal cortical capillaries in normal young controls (46-65 years of age) was estimated as 5.2 ± 0.2 per mm capillary length. This number was reduced by 45% in older controls (> 78 years) to 2.9 ± 0.1 per mm capillary length (P < 0.001). We further found that the numbers of pericyte cell bodies per COL4 mm2 area or per mm capillary length were not decreased but rather preserved or increased in PSD, AD and Mixed dementia groups compared to similar age older controls (P < 0.01). Consistent with this, we noted that capillary length densities identified by the endothelial marker glucose transporter 1 or COL4 were not different across the dementias compared to older controls. There was a negative correlation with age (P < 0.001) suggesting fewer pericyte somata in older age, although the % COL4 immunoreactive capillary area was increased in older controls compared to young controls. Using a proven reliable method to quantify COL4-positive nucleated pericytes, our observations demonstrate ageing related loss but mostly preserved pericytes in the frontal cortex of vascular and AD dementias. We suggest there is differential regulation of capillary pericytes in the frontal lobe between the cortex and white matter in ageing-related dementias.

Project description:BackgroundEribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a tubulin-binding drug and approved in many countries worldwide for treatment of certain patients with advanced breast cancer. Here we investigated antiproliferative and antiangiogenic effects of eribulin on vascular cells, human umbilical vein endothelial cells (HUVECs) and human brain vascular pericytes (HBVPs), in vitro in comparison with another tubulin-binding drug, paclitaxel.MethodsHUVECs and HBVPs were treated with either eribulin or paclitaxel and their antiproliferative effects were evaluated. Global gene expression profiling changes caused by drug treatments were studied using Affymetrix microarray platform and custom TaqMan Low Density Cards. To examine effects of the drugs on pericyte-driven in vitro angiogenesis, we compared lengths of capillary networks in co-cultures of HUVECs with HBVPs.ResultsBoth eribulin and paclitaxel showed potent activities in in vitro proliferation of HUVECs and HBVPs, with the half-maximal inhibitory concentrations (IC50) in low- to sub-nmol/L concentrations. When gene expression changes were assessed in HUVECs, the majority of affected genes overlapped for both treatments (59%), while in HBVPs, altered gene signatures were drug-dependent and the overlap was limited to just 12%. In HBVPs, eribulin selectively affected 11 pathways (p < 0.01) such as Cell Cycle Control of Chromosomal Replication. In contrast, paclitaxel was tended to regulate 27 pathways such as PI3K/AKT. Only 5 pathways were commonly affected by both treatments. In in vitro pericyte-driven angiogenesis model, paclitaxel showed limited activity while eribulin shortened the formed capillary networks of HUVECs driven by HBVPs at low nmol/L concentrations starting at day 3 after treatments.ConclusionsOur findings suggest that pericytes, but not endothelial cells, responded differently, to two mechanistically-distinct tubulin-binding drugs, eribulin and paclitaxel. While eribulin and paclitaxel induced similar changes in gene expression in endothelial cells, in pericytes their altered gene expression was unique and drug-specific. In the functional endothelial-pericyte co-culture assay, eribulin, but not paclitaxel showed strong efficacy not only as a cytotoxic drug but also as a potent antivascular agent that affected pericyte-driven in vitro angiogenesis.

Dataset Information

Denser brain capillary network with preserved pericytes in Alzheimer's disease.

Publications

Denser brain capillary network with preserved pericytes in Alzheimer's disease.

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