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Global Translational Medicine Traumatic memories in PTSD

1. Introduction cleavage brought furin to the forefront of bioweapon
research, where it remains up to the present day. 20-23
Post-traumatic stress disorder (PTSD) is characterized by
numerous memory-related symptoms, including traumatic In lipid metabolism, furin activates lipoprotein lipase
amnesia, hypermnesia, and intrusive thoughts related to (LPL), an enzyme that regulates the plasma levels of
the traumatic event. 1 triglycerides and high-density lipoproteins (HDL). Both
triglycerides and HDLs have been implicated in stress-
Cerebral endothelial cells (CECs) are an important 24
source of brain-derived neurotrophic factor (BDNF), related disorders, including PTSD.
producing 50 times more BDNF levels than neurons, Interest in furin resurfaced during the COVID-19
suggesting that these cells play a substantial role in pandemic, as the virus exploits this protein to increase
PTSD. In fact, BDNF regulates stress hormones and the infectivity. Nevertheless, the viral exploitation of furin
2-4
vulnerability to stress-related disorders. BDNF level is disrupts plasmin and BDNF, potentially predisposing
2
elevated in the peripheral blood of patients with PTSD and individuals to PTSD. Hence, COVID-19 was associated
25
is believed to be a biomarker of this pathology. with a higher prevalence of PTSD, as this condition was
The BDNF receptor tropomyosin receptor kinase B promoted by excessive isolation and lockdown as well as
26
(Trk-B) is crucial for neuronal plasticity, survival, and furin disruption and altered BDNF levels. Furthermore,
growth as well as for long-term potentiation (LTP). In because BDNF is a part of the SASP, its elevated levels in the
5
27
contrast, the receptor for pro-BDNF, the p75 neurotrophin peripheral blood of patients with PTSD may be explained.
receptor (p75NTR), which mediates the apoptosis of We suggest that non-cerebral BDNF is detrimental and likely
hippocampal and amygdalar neurons, probably accounts induces cellular senescence, including cognitive deficit.
for the brain volume reduction in patients with PTSD. In Psychological stress is associated with premature
6
fact, a study in neuroimaging has associated PTSD with cellular aging, a phenotype characteristic of several
brain volume loss, involving the hippocampus, amygdala, mental illnesses, including schizophrenia (SCZ) and
insular cortex, and anterior cingulate cortex, suggesting PTSD. Psychological stress triggers sterile inflammation,
that these areas suppress traumatic memories. 7 activation of the NOD-like receptor family pyrin domain-
CECs express abundant monocarboxylate transporter containing 3 (NLRP3) inflammasome, and generation
(MCT), a lactate-transporting molecule because these cells of interleukin (IL)-1) and IL-18, a family of cytokines
utilize lactate as their primary energy source. A recent associated with neuroinflammation, anxiety, or psychosis. 28
8,9
study linked lactate to spatial memory enhancement, In this narrative review, we explore the existing
suggesting a beneficial effect of glycolysis on the brain. knowledge regarding senescent ECs in PTSD and
Conversely, lactylation, a post-translational modification discuss several natural and synthetic compounds that
of histone protein lysine residues (Kla), is associated with may counteract endothelial senescence, SASP, and
neuropsychiatric disorders, including PTSD. Moreover, mitochondrial transplant or transfer.
10
our research group reported an association between
lactylation and the pathogenesis of traumatic memories in 2. Traumatic memories are decentralized
patients with PTSD. 11
Unlike conventional memories, traumatic imprinting
CECs regulate blood flow to the brain and interact is believed to occur in the right amygdala and posterior
with the surrounding parenchyma, playing a significant cingulate cortex. 29,30 Here, emotionally charged memories
role in the pathogenesis of dementia and further linking are processed without the involvement of the hippocampus
memory to endothelia. Senescent CECs represent a and are experienced as though they occur in the present
12
significant burden of senescent cells in the body. Excessive moment. Recent studies have demonstrated that
31
lactate production links these senescent ECs to PTSD and dysfunctional peripheral blood mononuclear cells could
cardiovascular disease (CVD). 13-16 cause or exacerbate PTSD, suggesting that extracerebral cells
The proprotein convertase subtilisin/kexin family and tissues are detrimental to traumatic recall. 32,33 This raises
member 3 (FURIN), a newly identified player in the question, can cognition generally “dwell” in peripheral
neuropsychiatric illness, is highly expressed in CECs and tissues? In fact, early studies have found that single cells or
plays a vital role in cellular senescence by interfering with unicellular life forms can process and recall information. 34,35
BDNF maturation. 17-19 Furin is a proprotein convertase 2.1. What is decentralized cognition?
that transforms precursor proteins into biologically active
forms, including pro-BDNF into BDNF. Its ability to Cognition and memory are precious human assets that
activate toxins or pathogens, such as anthrax, by proteolytic make us unique and distinct from other species. Therefore,

Volume 3 Issue 4 (2024) 2 doi: 10.36922/gtm.3974