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Global Translational Medicine Traumatic memories in PTSD

4.1. Like good and bad cholesterol, there is good collective memories of anthrax weaponization programs
and bad BDNF and the discovery of FURIN in 1990 raised the question
BDNF can positively and negatively affect human health. of whether other pathogens, especially viruses, could be
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We hypothesize that there are two sources of BDNF: manipulated to increase infectivity (gain of function).
cerebral cells and extracerebral cells. With senescence, Nonetheless, despite the pandemic and reemergent
each group of cells produces even more BDNF. worldwide concerns regarding the weaponization of this
Normal BDNF promotes LTP, learning, memory, and virus, COVID-19 contributed to a better understanding
euthymic mood. The “good” BDNF is neuroprotective, of furin, the convertase usurped by the SARS-CoV-2
preventing neurodegenerative diseases, and is upregulated to cleave the S (spike) protein into S1 and S2, thereby
by exercise. In contrast, the “bad” BDNF, an SASP increasing infectivity. An arginine-rich sequence, PRRAR
component, promotes long-term depression (LTD), (proline–arginine–arginine–alanine–arginine), which
dysthymic mood, premature senescence, and learning hijacks human furin, facilitates the viral morbidity of
difficulties. SARS-CoV-2.
Both the “good” and “bad” BDNF forms are probably In neuropsychiatric illness, the levels of furin,
tumorigenic. Therefore, cancer cells, including HeLa cells, previously implicated in SMI, decrease in patients with
overexpress BDNF-associated furin. 52 SCZ, dementias, and PTSD and increase in patients with
epilepsy, suggesting a novel neuropsychiatric target. 82-84
4.2. Psychological stress and vascular aging Furthermore, as furin is intertwined with the serotonergic
system, increased BDNF levels can contribute to the
Cellular senescence, the building block of organismal spread of fear-mediated behavior. Furthermore, several
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aging, is a default program of replicative arrest in cancers upregulate BDNF, probably due to its angiogenetic
which cells permanently exit the cell cycle, rewire their properties, which may facilitate metastatic dissemination.
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metabolism, and secrete SASP. When DNA damage is In fact, because ECs release large amounts of BDNF, their
substantial, the cell activates the senescence program,
and repairing the genome requires replicative arrest. exploitation can result in the total control of this growth
75
factor.
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Senescence affects ECs first, probably to increase the
levels of BDNF, an angiogenesis-promoting neurotrophin Pro-BDNF acts on p75NTR, whereas BDNF interacts
that facilitates the sprouting of new vessels to replace the with Trk-B. The former induces LTD, whereas the latter
damaged ones. 25,76-78 In fact, senescent cells upregulate induces LTP, learning, and memory. LTP promotes the
BDNF because this growth factor is a component of growth of neurites and dendritic spines, increasing the
the SASP and is spread locally in a paracrine/exocrine gray matter volume and lowering aggressive behavior. 87,88
manner. In PTSD, a condition marked by premature We shall next focus on PTSD and the most recent
20
cellular senescence, BDNF levels are probably elevated molecular and clinical insights.
due to cellular senescence. 79
BDNF is derived from pro-BDNF, an inactive precursor 4.3. Do microtubules encode traumatic memories?
protein that requires proteolytic cleavage by furin or Upregulated BDNF interacts with Trk-B, inhibiting
plasmin to be converted into the biologically active form. glycogen synthase kinase-3 (GSK-3), an enzyme implicated
Furin protein, encoded by FURIN, is a calcium (Ca )- in cellular senescence that is overactive in patients with SCZ,
2+
dependent serine protease that plays a vital role in the PTSD, bipolar disorder, and dementias (approximately
activation of numerous endogenous and exogenous 10% of patients with frontotemporal dementia behavioral
proteins into functional molecules. Furin and plasmin variant exhibit dysfunctional GSK-3β). In fact, GSK-3β (also
activate BDNF, whereas plasminogen activator inhibitor-1 termed tau kinase) promotes the hyperphosphorylation of
(PAI-1) inhibits plasmin and suppresses the proteolytic tau (p-tau), a marker of tauopathies, including Alzheimer’s
activity of furin. 80 disease (AD). In patients with PTSD, GSK-3β and p-tau
Over the past few decades, furin has attracted the levels are elevated; however, in patients with SCZ, both tau
attention of researchers and clinicians for two reasons; and p-tau levels are decreased. 89
first, the weaponization of anthrax by the Soviet Union in Under physiological circumstances, tau is a microtubular
the 1950s and 1960s, and second, its vital role in COVID- stabilizer believed to participate in tubulin memory
19 infectivity. The former triggered an intensive biological storage and retrieval. Microtubules (MTs) are cytoskeletal
arms race, which stopped only after the “Sverdlovsk components formed by tubulin polymerization and held
anthrax outbreak of 1979” that killed 64 people. The together by tau. It was hypothesized that the MT lattices
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Volume 3 Issue 4 (2024) 5 doi: 10.36922/gtm.3974