Probable Reasons for Neuron Copper Deficiency in the Brain of Patients with Alzheimer’s Disease: The Complex Role of Amyloid

Alzheimer’s disease is a progressive neurodegenerative disorder that eventually leads the affected patients to die. The appearance of senile plaques in the brains of Alzheimer’s patients is known as a main symptom of this disease. The plaques consist of different components, and according to numerous reports, their main components include beta-amyloid peptide and transition metals such as copper. In this disease, metal dyshomeostasis leads the number of copper ions to simultaneously increase in the plaques and decrease in neurons. Copper ions are essential for proper brain functioning, and one of the possible mechanisms of neuronal death in Alzheimer’s disease is the copper depletion of neurons. However, the reason for the copper depletion is as yet unknown. Based on the available evidence, we suggest two possible reasons: the first is copper released from neurons (along with beta-amyloid peptides), which is deposited outside the neurons, and the second is the uptake of copper ions by activated microglia.

Potential neuroprotective of trans-resveratrol a promising agent tempeh and soybean seed coats-derived against beta-amyloid neurotoxicity on primary culture of nerve cells induced by 2-methoxyethanol

Resveratrol, a natural polyphenol found in tempeh, has not been investigated especially in vitro as a neuroprotective agent against 2-methoxyethanol (2-ME)-induced beta-amyloid cytotoxicity. Beta amyloid peptides (Aβ) could initiate neurotoxic events and neuron-inflammatory response via microglial activation. However, it remains unknown whether the neurotoxic effect of beta-amyloid and/or associated with the potential of 2-ME to induce neurotoxic effects on primary culture of nerve cells induced by 2-ME. This study investigated potential neuroprotective of trans-resveratrol a promising agent tempeh and soybean seed coats-derived against beta-amyloid cytotoxicity on primary culture of nerve cells induced by 2-methoxyethanol. Biotium and MTT assays were used to analyze neurons, which were isolated from the cerebral cortex of fetal mice at gestation day 19 (GD-19). A standard solution of 2-methoxyethanol was dosed at 10 μL. The cultured cells were randomly divided into the following groups: (1) 2-ME group + resveratrol standard, (2) 2-ME group + resveratrol isolated from tempeh, (3) 2-ME group + resveratrol isolated from soybean seed coats, and (4) the control group, without the addition of either 2-ME or resveratrol. Exposure of the primary cortical neuron cells to beta-amyloid monoclonal antibody pre-incubated for 24 h with 10 µL of 4.2 µg/mL resveratrol and 7.5 mmol/l 2-methoxy-ethanol additions. Here, we report that the addition of 2-ME and resveratrol (standard and isolated from tempeh) of cell culture at concentrations of 1.4, 2.8 and 4.2 µg/mL showed that the majority of neurons grew well. In contrast, after exposure to 2-ME and Beta-amyloid, showed that glial activated. These findings demonstrate a role for resveratrol in neuroprotective-neurorescuing action.

SARS-CoV-2 Exacerbates Beta-Amyloid Neurotoxicity, Inflammation and Oxidative Stress in Alzheimer’s Disease Patients

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered the pandemic Coronavirus Disease 19 (COVID-19), causing millions of deaths. The elderly and those already living with comorbidity are likely to die after SARS-CoV-2 infection. People suffering from Alzheimer’s disease (AD) have a higher risk of becoming infected, because they cannot easily follow health roles. Additionally, those suffering from dementia have a 40% higher risk of dying from COVID-19. Herein, we collected from Gene Expression Omnibus repository the brain samples of AD patients who died of COVID-19 (AD+COVID-19), AD without COVID-19 (AD), COVID-19 without AD (COVID-19) and control individuals. We inspected the transcriptomic and interactomic profiles by comparing the COVID-19 cohort against the control cohort and the AD cohort against the AD+COVID-19 cohort. SARS-CoV-2 in patients without AD mainly activated processes related to immune response and cell cycle. Conversely, 21 key nodes in the interactome are deregulated in AD. Interestingly, some of them are linked to beta-amyloid production and clearance. Thus, we inspected their role, along with their interactors, using the gene ontologies of the biological process that reveals their contribution in brain organization, immune response, oxidative stress and viral replication. We conclude that SARS-CoV-2 worsens the AD condition by increasing neurotoxicity, due to higher levels of beta-amyloid, inflammation and oxidative stress.

White Matter Beta-Amyloid Precursor Protein Immunoreactivity in Autopsied Subjects With and Without COVID-19

The coronavirus SARS-CoV-2 causes COVID-19, a predominantly respiratory disease that has been reported to be associated with numerous neurological signs, symptoms and syndromes. More than 20 published studies have used RT-PCR methods to determine viral SARS-CoV-2 genomic presence in postmortem brain tissue and the overall impression is that viral brain invasion is relatively uncommon and occurs in low copy numbers, supporting indirect mechanisms as the cause of most neurological phenomena. Hypoxic-ischemic brain injury and stroke are one such possible indirect mechanism, as acute ischemia or stroke concurrence with COVID-19 has been reported as being 0.5% to 20%. Immunohistochemical stains for beta-amyloid precursor protein (APP) have been suggested to be a signature change of hypoxic leukoencephalopathy or COVID-19 brain disease, although prior reports have not had a non-COVID-19 control group. We therefore compared the prevalence and intensity of white matter APP staining in the brains of subjects dying with and without COVID-19. Clinical and neuropathological results, including semi-quantitative assessment of the density of white matter APP staining, were compared between 20 COVID-19 cases and 20 pre-COVID-19 autopsy cases, including 10 cases with autopsy-proven non-COVID-19 pneumonia and 10 cases without pneumonia. Positive APP white matter staining in at least one of the two brain regions (precentral gyrus and cingulate gyrus) studied was not significantly more common in COVID-19 vs controls (14/20 vs 12/20). Comparing density scores from both brain regions combined, the mean scores for COVID-19 cases were higher than those for controls of both types together but not significantly different when restricting to controls with pneumonia. Among control cases, cases with pneumonia had significantly higher scores. The presence or absence of a major neuropathologically-defined neurodegenerative disorder did not significantly affect the APP scores. The major finding is that while APP white matter staining cannot be regarded as a specific marker of COVID-19, as it does not occur with significantly greater probability in in COVID-19 brains as compared to non-COVID-19 brains, it is possible that white matter APP staining, representing acute or subacute axonal damage, may be a common occurrence in the perimortem period, and that it may be more intense in subjects dying with pneumonia, regardless of cause.

A histopathological comparison of prophylactic effects of Rosmarinic Acid and Oleanolic Acid isolated from Salvia species (sage) in scopolamine induced dementia model

Objective: Alzheimer's disease (AD) is the most common form of dementia, can be created in experimental models by using toxins. Possible therapeutic effects of secondary metabolites Rosmarinic (RA) and Oleanolic acids (OA) obtained from Salvia species (sage) were investigated using histopathological and immunohistochemical tecniques in experimental Alzheimer's-like dementia model induced by scopolamine. Study Design: Male BALB/c mice (n: 48) of 3-4 weeks old, divided into 6 groups; control received only saline(i.p.) for 21 days, scopolamine group received 3 mg/kg of scopolamine (i.p.) between 8-21th days. Scopolamine + RA group received 5 mg/kg RA (i.p.) between days 0 and 21 and 3 mg/kg of scopolamine (i.p.) between 8-21th days. Scopolamine + OA group received 5 mg/kg of OA (i.p.) between days of 0-21 and 3 mg/kg of scopolamine (i.p.) between 8-21th days. RA group received 5 mg/kg RA (i.p.) between 0-21th days. OA group received 5 mg/kg of OA (i.p.) between 0-21th days. Animals were sacrificed under anesthesia, brain tissues were excised and placed in 10% formaldehyde, embedded in paraffin wax. 5 µm sections were cut, stained for histopathological examinations. Immunoreactivity for Beta-amyloid accumulation was observed. ImageJ 153 software was used to analyze IHC figures. Positive signaling for DAB density was calculated, ANOVA test with the post hoc dunnett's or tukey test were applied, p<0.05 was considered statistically significant. Results: In scopolamine+RA treated group, tissue degeneration was less compared to the scopolamine group. Scopolamine+OA group revealed signs of pyknosis in neurons. The amyloid beta immunoexpression was positive in scopolamine group partially positive in scopolamine+OA group but, negative in RA treated scopolamine group. Intensity of signal in scopolamine group was statistically increased compared to control (p=0.0102). Intensity of signal was reduced in Scopolamine+RA and Scopolamine+OA groups, was statistically significant (p=0.0281 and p=0.0362, respectively). Conclusion: We suggest that pretreatment of RA and OA decreased beta amyloid formation and ameliorated tissue structure but, further studies with different methods are needed to be commercially available. Keywords: Scopolamine, dementia, Rosmarinic acid, Oleanolic acid, histopathology, Amyloid beta