“It turned out that the pericytes from the ApoE4 cells drastically increased their expression level of ApoE,” said Li-Huei Tsai, Picower Professor of Neuroscience and Director of the Picower Institute For Learning and Memory at MIT.
The scientists then identified a pathway that elevated ApoE expression, triggering more beta-amyloid to accumulate.
“The reason why knowing the pathway is important is because we already have FDA-approved small molecules that can inhibit this pathway,” Tsai said.
One of the FDA-approved drugs that the team tested is currently used to prevent organs from shrinking after transplants. And Tsai pointed to an intriguing finding from past studies: “There are known publications following those individuals who received organ transplant under medication with this drug,” Tsai said. “These people turned out to have a much reduced incident of developing dementia.”
deborahk wrote:Meanwhile, the researchers found that the drug reduced the levels of ApoE proteins and the buildup of beta-amyloid after administering it in mice and blood-brain barrier models.
antimatter37 wrote:The basic conclusion that these authors reach is that APOE4 types suffer greater BBB breakdown over time than their APOE3 cohorts, owing primarily to the degradation in pericyte function surrounding the brain blood vessels. This BBB breakdown leads to cognitive impairment in the APOE4 individuals but is NOT correlated with increased levels of AB or TAU in the APOE4 brains.
SusanJ wrote:Do you know what drug they were looking at? The paper is behind a paywall...
In Alzheimer’s disease, amyloid deposits along the brain vasculature lead to a condition known as cerebral amyloid angiopathy (CAA), which impairs blood–brain barrier (BBB) function and accelerates cognitive degeneration. Apolipoprotein (APOE4) is the strongest risk factor for CAA, yet the mechanisms underlying this genetic susceptibility are unknown. Here we developed an induced pluripotent stem cell-based three-dimensional model that recapitulates anatomical and physiological properties of the human BBB in vitro. Similarly to CAA, our in vitro BBB displayed significantly more amyloid accumulation in APOE4 compared to APOE3. Combinatorial experiments revealed that dysregulation of calcineurin–nuclear factor of activated T cells (NFAT) signaling and APOE in pericyte-like mural cells induces APOE4-associated CAA pathology. In the human brain, APOE and NFAT are selectively dysregulated in pericytes of APOE4 carriers, and inhibition of calcineurin–NFAT signaling reduces APOE4-associated CAA pathology in vitro and in vivo. Our study reveals the role of pericytes in APOE4-mediated CAA and highlights calcineurin–NFAT signaling as a therapeutic target in CAA and Alzheimer’s disease.
... [from the body of the paper] ...
Inhibition of calcineurin reduces APOE expression and ameliorates Aβ deposition. To determine whether dysregulation of NFAT–calcineurin signaling in APOE4 pericytes contributes to upregulated APOE expression, we inhibited calcineurin signaling in iMCs using the well-established calcineurin inhibitors cyclosporine A (CsA) (2 μM), FK506 (5 μM) and INCA6 (5 μM) (Extended Data Fig. 7a). After 2 weeks, each of the three inhibitors significantly reduced APOE expression in APOE4/4 iMCs as measured by qRT–PCR (Fig. 5a). Calcineurin inhibition did not significantly reduce constitutively expressed proteins such as PGK1, HPRT and GAPDH, suggesting that APOE downregulation is not due to cellular death or global transcriptional repression (Extended Data Fig. 7b). APOE3/4 heterozygous iMCs also exhibited a significant reduction in APOE mRNA expression when treated with each of the three calcineurin inhibitors (Fig. 5b). Calcineurin inhibition reduced intracellular APOE protein as measured by immunofluorescence in both APOE4/4 homozygous and APOE3/4 heterozygous iMCs (Extended Data Fig. 7c,d). Likewise, CsA significantly reduced the concentration of soluble APOE protein in iMC medium measured by ELISA (Fig. 5c).
Here, we developed and validated a human in vitro model of the BBB. While the iBBB recapitulates numerous molecular and physiological features of the in vivo BBB there are clear differences that will benefit from future studies incorporating additional physiological aspects of the BBB and improving the fidelity of iPSC-derived vascular cells. This study revealed that NFAT-mediated upregulation of APOE in human pericytes underlies the pathogenic effects of APOE4 in CAA. We pinpoint that APOE and NFAT are dysregulated in human pericytes in the PFC and hippocampus of APOE4 carriers. We establish that chemical inhibition of calcineurin in APOE4 iMCs reduces APOE mRNA and protein and leads to reduced vascular amyloid accumulation. In vivo administration of calcineurin/NFAT inhibitors to APOE4 AD mice also markedly reduced APOEexpression and vascular amyloid. Interestingly, patients chronically administered CsA or FK506 have long been observed to have significantly lower incidence of dementia compared to the general population. Our results provide new insight into these observations and highlight APOE and calcineurin–NFAT-signaling as potential targets in APOE4-mediated CAA and AD.
LaderaJim wrote:Here is a link to to the USC research news release regarding APOE4 and the BBB damage that leads to AD.
I am particularly keen on this topic because I have APOE 4/4 and two cavernomas which are probably subject to the same problem of 'leaky capillaries' (causing my headaches) for which there seems to be no treatment available - LaderaJim
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