Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

Most traumatic brain injuries (TBIs) during military deployment or training are clinically “mild” and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation.

Polyphenols from Traditional Chinese Medicine and Mediterranean Diet are effective against Aβ toxicity in vitro and in vivo in Caenorhabditis elegans

The potential of naturally-occurring polyphenols as nutraceuticals to prevent and/or treat Alzheimer’s disease is studied. Five structurally related flavones and four tyrosols were tested in vitro in human amyloid-β peptide...

Immunotherapeutic Approaches for the Treatment of Neurodegenerative Diseases: Challenges and Outcomes

Background: Neurodegenerative diseases, being rapidly increasing disorders and the seventh leading cause of death worldwide, have been a great challenge for researchers, affecting cognition, motor activity and other body functioning due to neurodegeneration. Several neurodegenerative diseases are caused by aggregation of proteins which induce the alteration of neuronal function leading to cell death. These proteins are amyloid-β peptide, tau, α-synuclein, and mHTT, which cause Alzheimer’s disease, Frontotemporal dementia, Corticobasal degeneration, Progressive supranuclear palsy, Parkinson’s disease, Multiple system atrophy, Dementia with Lewy-body and Huntington’s disease. Currently available treatments only reduce symptoms and increase life sustainability; however, they possess side effects and are ineffective in curing the diseases. Objectives: Literature survey of neurodegenerative diseases and immunotherapeutic approaches used to evaluate their pharmacological effects and future endeavours. Methods: A literature search was performed to find the relevant articles related to neurodegenerative diseases and immunotherapies. Clinical trials data were analysed from clinicaltrial.com. Result: According to literature study, it was found that researchers have explored the effect of active and passive vaccines generated against amyloid-β, tau, α-synuclein and mHTT. Few clinical trials have shown severe side effects and terminated, despite of that, few of them produced desirable effects for the treatment of AD and PD. Conclusion: Several immunotherapeutic trials have shown promising outcomes against amyloid-β, tau and α-synuclein. In addition, various preclinical studies against mHTT and prion proteins are under scrutinization. These clinical outcomes indicate promising role of immunotherapies against neurodegenerative diseases.

Sialic Acid Ameliorates Cognitive Deficits by Reducing Amyloid Deposition, Nerve Fiber Production, and Neuronal Apoptosis in a Mice Model of Alzheimer’s Disease

(1) Background: As a natural carbohydrate, sialic acid (SA) is helpful for brain development, cognitive ability, and the nervous system, but there are few reports about the effect of SA on Alzheimer’s disease (AD). (2) Method: The present study evaluated the effect of SA on cognitive ability, neuronal activity, Aβ formation, and tau hyperphosphorylation in a double transgenic AD (2×Tg-AD) mice model. The 2×Tg-AD mice were randomly divided into four groups: the AD control group, 17 mg/kg SA-treated AD group, 84 mg/kg SA-treated AD group, and 420 mg/kg SA-treated AD group. Mice from all four groups were fed to 7 months of age for the behavioral test and to 9 months of age for the pathological factors investigation. (3) Results: In the Morris water maze, the escape latency significantly decreased on the fifth day in the SA-treated groups. The number of rearing and crossing times in the open field test also increased significantly, compared with the control group. SA treatment significantly reduced amyloid β-peptide (Aβ) and nerve fibers and increased the number of Nissl bodies in the brain of AD mice. (4) Conclusions: SA reduced the neuron damage by reducing Aβ and inhibited tau protein hyperphosphorylation, which improved the cognitive ability and mobility of AD mice.

Neurodegeneration and Astrogliosis in the Human ca1 Hippocampal Subfield Are Related to hsp90ab1 and bag3 in Alzheimer’s Disease

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is characterized by executive dysfunction and memory impairment mediated by the accumulation of extracellular amyloid-β peptide (Aβ) and intracellular hyperphosphorylated tau protein. The hippocampus (HIPP) is essential for memory formation and is involved in early stages of disease. In fact, hippocampal atrophy is used as an early biomarker of neuronal injury and to evaluate disease progression. It is not yet well-understood whether changes in hippocampal volume are due to neuronal or glial loss. The aim of the study was to assess hippocampal atrophy and/or gliosis using unbiased stereological quantification and to obtain hippocampal proteomic profiles related to neurodegeneration and gliosis. Hippocampal volume measurement, stereological quantification of NeuN-, Iba-1- and GFAP-positive cells, and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS) analysis were performed in AD and non-AD cases. Reduced hippocampal volume was identified using the Cavalieri probe, particularly in the CA1 region, where it correlated with neuronal loss and astrogliosis. A total of 102 downregulated and 47 upregulated proteins were identified in the SWATH-MS analysis after restrictive filtering based on an FC >1.5 and p value < 0.01. The Hsp90 family of chaperones, particularly BAG3 and HSP90AB1, are closely related to astrocytes, indicating a possible role in degrading Aβ and tau through chaperone-mediated autophagy.

Hybrid Bis-Histidine Phenanthroline-Based Ligands to Lessen Aβ-Bound Cu ROS Production: An Illustration of Cu(I) Significance

We here report the synthesis of three new hybrid ligands built around the phenanthroline scaffold and encompassing two histidine-like moieties: phenHH, phenHGH and H’phenH’, where H correspond to histidine and H’ to histamine. These ligands were designed to capture Cu(I/II) from the amyloid-β peptide and to prevent the formation of reactive oxygen species produced by amyloid-β bound copper in presence of physiological reductant (e.g., ascorbate) and dioxygen. The amyloid-β peptide is a well-known key player in Alzheimer’s disease, a debilitating and devasting neurological disorder the mankind has to fight against. The Cu-Aβ complex does participate in the oxidative stress observed in the disease, due to the redox ability of the Cu(I/II) ions. The complete characterization of the copper complexes made with phenHH, phenHGH and H’phenH’ is reported, along with the ability of ligands to remove Cu from Aβ, and to prevent the formation of reactive oxygen species catalyzed by Cu and Cu-Aβ, including in presence of zinc, the second metal ions important in the etiology of Alzheimer’s disease. The importance of the reduced state of copper, Cu(I), in the prevention and arrest of ROS is mechanistically described with the help of cyclic voltammetry experiments.

Severe Gestational Low-Protein Intake Impacts Hippocampal Cellularity, Tau, and Amyloid-β Levels, and Memory Performance in Male Adult Offspring: An Alzheimer-Simile Disease Model?

Background: Maternal undernutrition has been associated with psychiatric and neurological disorders characterized by learning and memory impairment. Objective: Considering the lack of evidence, we aimed to analyze the effects of gestational protein restriction on learning and memory function associated with hippocampal cell numbers and neurodegenerative protein content later in life. Methods: Experiments were conducted in gestational low- (LP, 6% casein) or regular-protein (NP, 17% casein) diet intake offspring. Behavioral tests, isolated hippocampal isotropic fractionator cell studies, immunoblotting, and survival lifetime were observed. Results: The birthweight of LP males is significantly reduced relative to NP male progeny, and hippocampal mass increased in 88-week-old LP compared to age-matched NP offspring. The results showed an increased proximity measure in 87-week-old LP compared to NP offspring. Also, LP rats exhibited anxiety-like behaviors compared to NP rats at 48 and 86-wk of life. The estimated neuron number was unaltered in LP rats; however, non-neuron cell numbers increased compared to NP progeny. Here, we showed unprecedented hippocampal deposition of brain-derived neurotrophic factor, amyloid-β peptide (Aβ), and tau protein in 88-week-old LP relative to age-matched NP offspring. Conclusion: To date, no predicted studies showed changes in hippocampal morphological structure in maternal protein-restricted elderly offspring. The current data suggest that gestational protein restriction may accelerate hippocampal function loss, impacting learning/memory performance, and supposedly developing diseases similar to Alzheimer’s disease (AD) in elderly offspring. Thus, we propose that maternal protein restriction could be an elegant and novel method for constructing an AD-like model in adult male offspring.