Alzheimer’s disease (AD) is a disorder that causes degeneration of the cells in the brain and it is the main cause of dementia, which is characterized by a decline in thinking and independence in personal daily activities. AD is considered a multifactorial disease: two main hypotheses were proposed as a cause for AD, cholinergic and amyloid hypotheses. Additionally, several risk factors such as increasing age, genetic factors, head injuries, vascular diseases, infections, and environmental factors play a role in the disease. Currently, there are only two classes of approved drugs to treat AD, including inhibitors to cholinesterase enzyme and antagonists to N-methyl d-aspartate (NMDA), which are effective only in treating the symptoms of AD, but do not cure or prevent the disease. Nowadays, the research is focusing on understanding AD pathology by targeting several mechanisms, such as abnormal tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage, aiming to develop successful treatments that are capable of stopping or modifying the course of AD. This review discusses currently available drugs and future theories for the development of new therapies for AD, such as disease-modifying therapeutics (DMT), chaperones, and natural compounds.

Comprehensive Review on Alzheimer’s Disease: Causes and Treatment

There has been a steep increase in allergic and autoimmune diseases, reaching epidemic proportions and now affecting more than one billion people worldwide. These diseases are more common in industrialized countries, and their prevalence continues to rise in developing countries in parallel to urbanization and industrialization. Intact skin and mucosal barriers are crucial for the maintenance of tissue homeostasis as they protect host tissues from infections, environmental toxins, pollutants and allergens. A defective epithelial barrier has been demonstrated in allergic and autoimmune conditions such as asthma, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, coeliac disease and inflammatory bowel disease. In addition, leakiness of the gut epithelium is also implicated in systemic autoimmune and metabolic conditions such as diabetes, obesity, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and autoimmune hepatitis. Finally, distant inflammatory responses due to a ‘leaky gut’ and microbiome changes are suspected in Alzheimer disease, Parkinson disease, chronic depression and autism spectrum disorders. This article introduces an extended ‘epithelial barrier hypothesis’, which proposes that the increase in epithelial barrier-damaging agents linked to industrialization, urbanization and modern life underlies the rise in allergic, autoimmune and other chronic conditions. Furthermore, it discusses how the immune responses to dysbiotic microbiota that cross the damaged barrier may be involved in the development of these diseases. In this review, Cezmi Akdis discusses how epithelial barrier-damaging agents linked to industrialization, urbanization and modern life may explain the increased prevalence of allergic disease as well as a wide range of autoimmune and metabolic conditions in which immune responses to translocated bacteria have systemic effects.

Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?

Heavy metal toxicity: An update of chelating therapeutic strategies

https://espace.library.uq.edu.au/view/UQ:d04f513/UQd04f513_OA.pdf

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation.

Neuro-inflammation and anti-inflammatory treatment options for Alzheimer's disease.

Alzheimer’s disease (AD) is a neurodegenerative disorder, most cases of which lack a clear causative event. This has made the disease difficult to characterize and, thus, diagnose. Although some cases are genetically linked, there are many diseases and lifestyle factors that can lead to an increased risk of developing AD, including traumatic brain injury, diabetes, hypertension, obesity, and other metabolic syndromes, in addition to aging. Identifying common factors and trends between these conditions could enhance our understanding of AD and lead to the development of more effective treatments. Although the immune system is one of the body’s key defense mechanisms, chronic inflammation has been increasingly linked with several age-related diseases. Moreover, it is now well accepted that chronic inflammation has an important role in the onset and progression of AD. In this review, the different inflammatory signals associated with AD and its risk factors will be outlined to demonstrate how chronic inflammation may be influencing individual susceptibility to AD. Our goal is to bring attention to potential shared signals presented by the immune system during different conditions that could lead to the development of successful treatments.

/pdf/inflammation-the-link-between-comorbidities-genetics-and-1vqgsj47a6.pdf

Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

Cognitive impairment in Alzheimer’s disease (AD) is associated with dysregulation of the RNA and protein expression profiles in the brain. Recent studies have highlighted the importance of RNA post-transcriptional regulation (epitranscriptomics) in higher order brain functions. Specifically, N6-methyladenosine (m6A), which controls RNA stability, splicing, translation and trafficking, plays an important role in learning and memory. This raises the question of whether m6A signaling is perturbed in AD. To address this, we investigated the expression profile of known m6A-regulatory genes using a public RNA-seq dataset and identified a subset of genes which were significantly dysregulated in the human AD brain. Among these, genes encoding the m6A methyltransferase, METTL3, and a member of the m6A methyltransferase complex (MACOM), RBM15B, were downregulated and upregulated in the hippocampus, respectively. These findings were validated at the protein level using an independent cohort of postmortem human brain samples. Unexpectedly, we observed an accumulation of methyltransferase-like 3 (METTL3), but not RBM15B, in the insoluble fractions, which positively correlated with the levels of insoluble Tau protein in the postmortem human AD samples. Aberrant expression and distribution of METTL3 in the hippocampus of the AD brain may therefore represent an epitranscriptomic mechanism underlying the altered gene expression patterns associated with disease pathogenesis.

Altered Expression of the m6A Methyltransferase METTL3 in Alzheimer's Disease.

As the understanding of immune responses in Alzheimer's disease (AD) is in its early phases, there remains an urgency to identify the cellular and molecular processes driving chronic inflammation. In AD, a subpopulation of astrocytes acquires a neurotoxic phenotype which prompts them to lose typical physiological features. While the underlying molecular mechanisms are still unknown, evidence suggests that myeloid differentiation primary response 88 (MyD88) adaptor protein may play a role in coordinating these cells' immune responses in AD. Herein, we combined studies in human postmortem samples with a conditional genetic knockout mouse model to investigate the link between MyD88 and astrocytes in AD. In silico analyses of bulk and cell‐specific transcriptomic data from human postmortem brains demonstrated an upregulation of MyD88 expression in astrocytes in AD versus non‐AD individuals. Proteomic studies revealed an increase in glial fibrillary acidic protein in multiple brain regions of AD subjects. These studies also showed that although overall MyD88 steady‐state levels were unaffected by AD, this protein was enriched in astrocytes near amyloid plaques and neurofibrillary tangles. Functional studies in mice indicated that the deletion of astrocytic MyD88 protected animals from the acute synaptic toxicity and cognitive impairment caused by the intracerebroventricular administration of β‐amyloid (Aβ). Lastly, unbiased proteomic analysis revealed that loss of astrocytic MyD88 resulted in altered astrocyte reactivity, lower levels of immune‐related proteins, and higher expression of synaptic‐related proteins in response to Aβ. Our studies provide evidence of the pivotal role played by MyD88 in the regulation of astrocytes response to AD.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/glia.24285

Judith Camats-Perna

Papers

Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation.

Altered Expression of the m6A Methyltransferase METTL3 in Alzheimer's Disease.

Deletion of MyD88 in astrocytes prevents β‐amyloid‐induced neuropathology in mice