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Purpose Psychological stress is a significant health problem in veterans and their family members. Traumatic brain injury (TBI) and stress lead to the onset, progression, and worsening of several inflammatory and neurodegenerative diseases in veterans and civilians. Alzheimer's disease (AD) is a progressive, irreversible neuroinflammatory disease that causes problems with memory, thinking, and behavior. TBIs and chronic psychological stress cause and accelerate the pathology of neuroinflammatory diseases such as AD. However, the precise molecular and cellular mechanisms governing neuroinflammation and neurodegeneration are currently unknown, especially in veterans. The purpose of this review article was to advance the hypothesis that stress and TBI-mediated immune response substantially contribute and accelerate the pathogenesis of AD in veterans and their close family members and civilians. Methods The information in this article was collected and interpreted from published articles in PubMed between 1985 and 2020 using the key words stress, psychological stress, Afghanistan war, Operation Enduring Freedom (OEF), Iraq War, Operation Iraqi Freedom (OIF), Operation New Dawn (OND), traumatic brain injury, mast cell and stress, stress and neuroimmune response, stress and Alzheimer's disease, traumatic brain injury, and Alzheimer's disease. Findings Chronic psychological stress and brain injury induce the generation and accumulation of beta-amyloid peptide, amyloid plaques, neurofibrillary tangles, and phosphorylation of tau in the brain, thereby contributing to AD pathogenesis. Active military personnel and veterans are under enormous psychological stress due to various war-related activities, including TBIs, disabilities, fear, new environmental conditions, lack of normal life activities, insufficient communications, explosions, military-related noise, and health hazards. Brain injury, stress, mast cell, and other immune cell activation can induce headache, migraine, dementia, and upregulate neuroinflammation and neurodegeneration in veterans of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn. TBIs, posttraumatic stress disorder, psychological stress, pain, glial activation, and dementia in active military personnel, veterans, or their family members can cause AD several years later in their lives. We suggest that there are increasing numbers of veterans with TBIs and stress and that these veterans may develop AD late in life if no appropriate therapeutic intervention is available. Implications Per these published reports, the fact that TBIs and psychological stress can accelerate the pathogenesis of AD should be recognized. Active military personnel, veterans, and their close family members should be evaluated regularly for stress symptoms to prevent the pathogenesis of neurodegenerative diseases, including AD.

The posterior parahippocampal gyrus (PPHG) of the non-human primate brain has a distinct dual role in cortical neural systems. On the one hand, it is a critical link in providing the entorhinal cortex and hippocampal formation with cortical input, while on the other hand it receives output from these structures and projects widely by disseminating the medial temporal lobe output to the cortex. Layer III of TF and TH areas (temporal areas F, H of von Economo and Koskinas (1925) and von Bonin and Bailey (1947) largely mediate the former (input) while layer V mediates the latter (output). We have examined areas TF and TH in the normal human brain and in Alzheimer’s disease (AD) using pathological stains (Nissl, Thioflavin S) and phenotype specific stains non-phosphorylated neurofilament protein (SMI-32) and parvalbumin (PV). Seven clinically and pathologically confirmed AD cases have been studied along with six age-compatible normal cases. Our observations reveal that neurofibrillary tangles (NFTs) heavily invest the area TF and TH neurons that form layers III and V. In both cortical areas, the large pyramids that form layer V contain a greater number of NFTs. These changes, and possibly, pyramidal cell loss, greatly alter the cytoarchitectural picture and diminish SMI-32 staining patterns. Layer III of area TH loses the majority of SMI-32 immunoreactivity, whereas this change is more conspicuous in layer V of area TF. PV-staining in both areas is largely unaffected. Normal cases contained no evidence of pathology or altered cytoarchitecture. These observations reveal a further disruption of memory related temporal neural systems in AD where pathology selectively alters both the input to the hippocampal formation and its output to the cortex.

Glia maturation factor (GMF), discovered and characterized in our laboratory, is a highly conserved protein primarily localized in mammalian central nervous system. Previously we demonstrated that GMF is required in the induced production of proinflammatory cytokines and chemokines in brain cells. We now report that ventricular infusion of human amyloid beta peptide1-42 (Abeta1-42) in mouse brain caused glial activation and large increases in the levels of GMF as well as induction of inflammatory cytokine/chemokine known for launching the neuro inflammatory cascade in Alzheimer's disease (AD). To test the hypothesis that GMF is involved in the pathogenesis of AD, we infused Abeta1-42 in the brain of GMF-deficient (GMF-KO) mice, recently prepared in our laboratory. GMF-deficient mice showed reduced glial activation and significantly suppressed proinflammatory cytokine/chemokine production following Abeta infusion compared to wild type (Wt) mice. The decrease in glial activation in the GMF-KO mice is also associated with significant reduction in Abeta induced loss of pre-synaptic marker, synaptophysin, and post-synaptic density protein-95 (PSD 95). We also examined the potential relationship between GMF or lack of it with learning and memory using the T-maze, Y-maze, and water maze, hippocampal-dependent spatial memory tasks. Our results show that memory retention was improved in GMF-KO mice compared to Wt controls following Abeta infusion. Diminution of these Abeta1-42 effects in primary cultures of GMF-KO astrocyte and microglia were reversed by reconstituted expression of GMF. Taken together, our results indicate a novel mediatory role of GMF in the neuro-inflammatory pathway of Abeta and its pro-inflammatory functions.

Human amniotic epithelial (HAE) cells are formed from amnioblasts, separated from the epiblast at about the 8th day after fertilization. We attempted to detect various developmental antigens specific to neural cells by immunocytochemical methods. The cultured HAE cells displayed positive immunoreactivity to RC1, vimentin, A2B5, neurofilament proteins, microtubule-associated protein 2 (MAP2) and MAP2 kinase. In addition, the cells also demonstrated immunoreactivity to glial fibrillary acidic protein, CNPase, myelin basic protein and galactocerebroside. The appearance rate of positive cells was more than 50% in cells positive to RC1, A2B5, vimentin or neuronal markers, and 20–30% to glial cell markers. Double staining showed the heterogeneous appearance of oligodendrocyte lineage cells. These data indicate that HAE cells may have the putative multipotentiality of neurons, astrocytes and oligodendrocytes.