Mount Sinai team reverses APOE4-driven scarring of brain blood vessels in aged mice

Pericytes normally keep small blood vessels stable and support the blood-brain barrier ^[4]. In the presence of APOE4, the Mount Sinai team found, they change into myofibroblast-like cells that produce scar tissue ^[4]. Part of the evidence is an atlas, built by combining existing datasets into one single-cell map of gene activity across the brain's vascular cells ^[3]. A gene-activity map shows association. On its own it cannot say the gene caused the switch.

The causal case rests on the intervention. TGF-beta signaling is involved in communication between cells and in tissue remodeling ^[16]. Blocking it restored pericyte coverage and reduced both fibrosis and amyloid around blood vessels ^[6]. The team then reproduced the result in aged APOE4 mice ^[7]. The lab also checked its findings in miBrains, its stem-cell-derived human brain tissue, against preclinical models, postmortem human brain tissue and transcriptomic data, using each to confirm the others ^[9].

Alzheimer's affects more than 7 million older adults in the United States ^[12]. Brain blood vessels are known to deteriorate as the disease progresses, especially in APOE4 carriers, and that damage has often been treated as a consequence of the disease ^[13]. "Damage to the brain's blood vessels is not simply a late consequence of Alzheimer's disease; it is a biologically active process caused by APOE4 that may be reversible," said Joel W. Blanchard, the corresponding author, of the Icahn School of Medicine at Mount Sinai ^[10].

For drug developers, the target this points to is the pericyte's conversion and the TGF-beta signal behind it. The measured benefit still includes amyloid, in the form of less of it around vessels after blockade ^[6]. "We show that APOE4 converts blood-vessel support cells into scar-producing cells, causing amyloid or abnormal protein buildup to accumulate around the brain's vessels," said Braxton R. Schuldt, the first author ^[11]. On that account the scarring comes first and the perivascular amyloid follows. A drug aimed at the switch would act upstream of amyloid and still be judged partly by it.

The thing this doesn't tell you is whether any of it changes how a brain works. The release says the vessel changes could interfere with blood flow ^[5]. It does not report how many mice were treated, how far fibrosis fell, or whether blood flow or memory improved after treatment. I think the reversal in aged animals is the strongest result in the package, on two conditions: that the effect sizes in the paper are large, and that restored pericyte coverage turns out to mean better circulation.

Mount Sinai's summary adds that APOE4 may sabotage the cellular systems that remove harmful proteins, and it names Parkinson's alongside Alzheimer's as diseases where the new targets could apply ^[14]. The second paper appeared in Cell Stem Cell ^[2]; the experiments described above come from the vessel study in Cell ^[3]. Mount Sinai says the miBrains platform could speed up the search for treatments ^[15].