Mitochondrial influences on blood brain barrier function and neuropsychiatric illness

Neuropsychiatric disorders are increasingly associated with neuroinflammatory processes. The blood-brain
barrier (BBB) is a critical modulator of peripheral inflammatory influences on brain development and function.
PIs Jorge Alvarez, a neuroimmunologist with expertise in the BBB, and Stewart Anderson, a developmental
neurobiologist with expertise in mechanisms of neuropsychiatric disorders, have recently demonstrated that the
BBB is compromised in a relatively common genetic cause of neuropsychiatric illness, the 22q11.2 deletion
syndrome (22qDS). While this finding in induced pluripotent stem cell (iPSC)-derived BBB-like cells (iBBB) and
in 22qDS model mice was initially ascribed mainly to haploinsufficiency of the BBB-enriched tight junction protein
claudin-5, work from the Anderson lab and others has also demonstrated that 22qDS is associated with
mitochondrial energetic compromise in various cell types. Since mitochondrial energetics are also necessary for
optimal BBB function, the PIs initiated experiments to determine whether mitochondrial energetics of the BBB
are compromised in 22qDS, whether this compromise is likely to influence BBB dysfunction in this disorder, and
whether correction of mitochondrial weakness improves BBB dysfunction in 22qDS. Remarkably, our preliminary
data strongly suggest that all three scenarios are true. If so, BBB energetics could be an underexplored
therapeutic target for neurodevelopmental and neurodegenerative disorders that involve inflammation.
Here, we propose to study the synergistic influences of structural and energetic compromise on BBB
function. Building upon our previous findings in iPSC-derived neurons and transformed blood cells, which
showed that 22qDS with schizophrenia (SZ) exhibits weaker mitochondrial energetics compared to 22qDS
without SZ or non-deleted controls, in Aim 1, we will investigate whether this association of mitochondrial
weakness and the presence of SZ in 22qDS extends to iBBB cells. We will also examine whether interventions
that enhance mitochondrial energetics improve BBB function, both in the 22qDS iBBB, and in 22qDS model
mice. In Aim 2 we will use a more reduced system, outside of the 22qDS context, to study whether OXPHOS
compromise will synergize with CLDN5 haploinsufficiency to generate greater BBB insufficiency. We will test
whether crossing mice heterozygous only for claudin-5 in the BBB with those lacking the mitochondrial-DNA
encoded gene ND6 will have exacerbated BBB dysfunction relative to each mutation alone. We will also test
whether enhancing mitochondrial energetics pharmacologically will rectify BBB dysfunction in the neurovascular
selective claudin-5 +/- mice.
In sum, the mitochondrial influence on BBB function is an underexplored area of study. Since these
influences are therapeutically targetable and since the influence of the BBB on neuroinflammation and brain
health is increasingly appreciated, this proposal could lead to important novel therapeutics both within and
beyond the 22qDS context.

Grant Number: 5R01MH134893-02
NIH Institute/Center: NIH
Principal Investigator: Jorge Alvarez