Tau protein is a microtubule-associated protein that is widely distributed in the central nervous system and maintains and regulates neuronal morphology and function. Tau protein aggregates abnormally and forms neurofibrillary tangles in neurodegenerative diseases, disrupting the structure and function of neurons and leading to neuronal death, which triggers the initiation and progression of neurological disorders. The aggregation of tau protein in neurodegenerative diseases is associated with post-translational modifications, which may affect the hydrophilicity, spatial conformation, and stability of tau protein, promoting tau protein aggregation and the formation of neurofibrillary tangles. Therefore, studying the role of tau protein in neurodegenerative diseases and the mechanism of aberrant aggregation is important for understanding the mechanism of neurodegenerative diseases and finding therapeutic approaches. This review describes the possible mechanisms by which tau protein promotes neurodegenerative diseases, the post-translational modifications of tau protein and associated influencing factors, and the current status of drug discovery and development related to tau protein, which may contribute to the development of new therapeutic approaches to alleviate or treat neurodegenerative diseases.

Non-enzymatic reaction involving carbonyl of reducing sugars and amino groups in proteins produces advanced glycation end products (AGEs). AGE accumulation in vivo is a crucial factor in the progression of metabolic and pathophysiological mechanisms like obesity, diabetes, coronary artery disease, neurological disorders, and chronic renal failure. The body\'s own defense mechanism, synthetic inhibitors, and natural inhibitors can all help to prevent the glycation of proteins. Synthetic inhibitors have the potential to suppress the glycation of proteins through a variety of pathways. They could avoid Amadori product development by tampering with the addition of sugars to the proteins. Besides which, the free radical scavenging and blocking crosslink formation could be another mechanism behind their anti-glycation properties. In comparison with synthetic substances, naturally occurring plant products have been found to be comparatively non-toxic, cheap, and usable in an ingestible form. This review gives a brief introduction of the Maillard reaction; formation, characterization and pathology related to AGEs, potential therapeutic approaches against glycation, natural and synthetic inhibitors of glycation and their probable mechanism of action. The scientific community could get benefit from the combined knowledge about important molecules, which will further guide to the design and development of new pharmaceutical compounds.

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets.

It is reported that approximately 40 million people are suffering from dementia, globally. Dementia is a group of symptoms that affect neurons and cause some mental disorders, such as losing memory. Alzheimer\'s disease (AD) which is known as the most common cause of dementia, is one of the top medical care concerns across the world. Although the exact sources of the disease are not understood, is it believed that aggregation of amyloid-beta (Aβ) outside of neuron cells and tau aggregation or neurofibrillary tangles (NFTs) formation inside the cell may play crucial roles. In this paper, we are going to review studies that targeted inhibition of amyloid plaque and tau protein tangle formation, to suppress or postpone AD.

The amyloidoses are a rare and heterogeneous group of disorders that are characterized by the deposition of abnormally folded proteins in tissues ultimately leading to organ damage. The deposits are mainly extracellular and are recognizable by their affinity for Congo red and their yellow-green birefringence under polarized light. Current classification of amyloid in medical practice is based on the amyloid protein type. To date, 36 proteins have been identified as being amyloidogenic in humans.
in clinical practice, it is critical to distinguish between treatable versus non-treatable amyloidoses. Moreover, amyloidoses with a genetic component must be distinguished from the sporadic types and systemic amyloidoses must be distinguished from the localized forms. Among the systemic amyloidoses, AL continues to be the most common amyloid diagnosis in the developed world; other clinically significant types include AA, ALECT2, and ATTR. The latter is emerging as an underdiagnosed type in both the hereditary and wild-type setting. Other hereditary amyloidoses include AFib, several amyloidoses derived from apolipoproteins, AGel, ALys, etc. In a dialysis setting, systemic amyloid derived from β2 microglobulin (Aβ2M) should be considered, although a very rare hereditary variant has also been reported; several amyloidoses may be typically associated with aging and several iatrogenic types have also emerged. Determination of the amyloid protein type is imperative before specific therapy can be implemented and the current methods are briefly summarized. A brief overview of the target organ involvement by amyloid type is also included. Key Messages: (1) Early diagnosis of amyloidosis continues to pose a significant challenge and requires the participation of many clinical and laboratory specialties. (2) Determination of the protein type is imperative before specific therapy can be implemented. (3) While mass spectrometry has emerged as the preferred method of amyloid typing, careful application of immune methods is still clinically useful but caution and experience, as well as awareness of the limitations of each method, are necessary in their interpretation. (4) While the spectrum of amyloidoses continues to expand, it is critical to distinguish between those that are currently treatable versus those that are untreatable and avoid causing harm by inappropriate treatment.

Over the recent years, Huntington\'s disease (HD) has become widely discussed in the scientific literature especially because at the mutant level there are several contradictions regarding the aggregation mechanism. The specific role of the physiological huntingtin protein remains unknown, due to the lack of characterization of its entire crystallographic structure, making the experimental and theoretical research even harder when taking into consideration its involvement in multiple biological functions and its high affinity for different interacting partners. Different types of models, containing fewer (not more than 35 Qs) polyglutamine residues for the WT structure and above 35 Qs for the mutants, were subjected to classical or advanced MD simulations to establish the proteins\' structural stability by evaluating their conformational changes. Outside the polyQ tract, there are two other regions of interest (the N17 domain and the polyP rich domain) considered to be essential for the aggregation kinetics at the mutant level. The polymerization process is considered to be dependent on the polyQ length. As the polyQ tract\'s dimension increases, the structures present more β-sheet conformations. Contrarily, it is also considered that the aggregation stability is not necessarily dependent on the number of Qs, while the initial stage of the aggregation seed might play the decisive role. A general assumption regarding the polyP domain is that it might preserve the polyQ structures soluble by acting as an antagonist for β-sheet formation.

Stroke and Alzheimer\'s disease (AD) are cerebral pathologies with high socioeconomic impact that can occur together and mutually interact. Vascular factors predisposing to cerebrovascular disease have also been specifically associated with development of AD, and acute stroke is known to increase the risk to develop dementia.Despite the apparent association, it remains unknown how acute cerebrovascular disease and development of AD are precisely linked and act on each other. It has been suggested that this interaction is strongly related to vascular deposition of amyloid-β (Aβ), i.e., cerebral amyloid angiopathy (CAA). Furthermore, the blood-brain barrier (BBB), perivascular space, and the glymphatic system, the latter proposedly responsible for the drainage of solutes from the brain parenchyma, may represent key pathophysiological pathways linking stroke, Aβ deposition, and dementia.In this review, we propose a hypothetic connection between CAA, stroke, perivascular space integrity, and dementia. Based on relevant pre-clinical research and a few clinical case reports, we speculate that impaired perivascular space integrity, inflammation, hypoxia, and BBB breakdown after stroke can lead to accelerated deposition of Aβ within brain parenchyma and cerebral vessel walls or exacerbation of CAA. The deposition of Aβ in the parenchyma would then be the initiating event leading to synaptic dysfunction, inducing cognitive decline and dementia. Maintaining the clearance of Aβ after stroke could offer a new therapeutic approach to prevent post-stroke cognitive impairment and development into dementia.

Alzheimer\'s disease (AD) is the most prevalent neurodegenerative disorder, with approximately 29 million older people suffering from this disease worldwide. This number is expected to become triple by 2050. AD is a complex and multifactorial neurodegenerative condition, characterized by complex pathology including oxidative stress, formation of aggregates of amyloid and tau, enhanced immune responses, metal deposition and disturbances in cholinesterase enzymes. There is no effective pharmacological treatment for combating the disease to date. The ineffectiveness of current pharmacological interventions in AD has led scientists to search for more safe and effective alternative therapeutic agents. Thus, natural products have become an important avenue for drug discovery in AD research. In this regard, polyphenols are natural products that have been shown to be effective in the modulation of the type of neurodegenerative changes seen in AD, suggesting a possible therapeutic role. The present review focuses on the chemistry of polyphenols, clinical studies for evaluating polyphenols as effective alternatives in AD treatment, cellular and molecular aspects of polyphenols in improving cognitive deficits and the current challenges and futuristic approaches to use polyphenols as safe and effective therapeutic agents in AD treatment.

Compelling evidence supports a tight link between oxidative stress and protein aggregation processes, which are noticeably involved in the development of proteinopathies, such as Alzheimer\'s disease, Parkinson\'s disease, and prion disease. The literature is tremendously rich in studies that establish a functional link between both processes, revealing that oxidative stress can be either causative, or consecutive, to protein aggregation. Because oxidative stress monitoring is highly challenging and may often lead to artefactual results, cutting-edge technical tools have been developed recently in the redox field, improving the ability to measure oxidative perturbations in biological systems. This review aims at providing an update of the previously known functional links between oxidative stress and protein aggregation, thereby revisiting the long-established relationship between both processes.

The neural dysfunction is triggered by cellular and molecular events that provoke neurotoxicity and neural death. Currently, neurodegenerative diseases are increasingly common, and available treatments are focused on relieving symptoms. Based on the above, in this review we describe the participation of vitexin in the main events involved in the neurotoxicity and cell death process, as well as the use of vitexin as a therapeutic approach to suppress or attenuate neurodegenerative progress. Vitexin contributes to increasing neuroprotective factors and pathways and counteract the targets that induce neurodegeneration, such as redox imbalance, neuroinflammation, abnormal protein aggregation, and reduction of cognitive and/or motor impairment. The results obtained provide substantial evidence to support the scientific exploration of vitexin in these pathologies, since their effects are still little explored for this direction.