Relationship periodontitis and Alzheimer's disease: Relevant aspects from an epigenetic view.

Neurodegenerative disorders are defined as hereditary and sporadic conditions which are characterized by progressive loss of structure or function of neurons in sensory, motor, and cognitive systems. Alzheimer's disease, Parkinson's disease, and depression are well-known examples of neurodegenerative disorders. The World Health Organization estimates that, by 2040, neurodegenerative diseases will surpass cancer as the principal cause of death in industrialized countries. Despite various advances in the understanding of the diseases, pharmacological treatment by conventional medicine has not obtained satisfactory results. Therefore, complementary and alternative medicine (CAM) can be a potential candidate for the preventative treatment of the disorders. The aim of this special issue is to demonstrate the clinical evidence and explore the acting mechanisms of CAM in treating neurodegenerative disorders. Alzheimer's disease is a well-recognized neurodegenerative disease characterized by a progressive deterioration of cognitive function and memory. At present, there are no effective treatments that can stop or reverse the progression of the disease. Pharmaceutical interventions that aim to delay the deterioration of this disease have been extensively studied. Although cholinesterase inhibitors and an N-methyl-D-aspartate receptor antagonist have been widely used for treating the syndromes of the disease, these drugs have not shown promising results and their uses are always limited by their undesirable side effects. In this special issue, several studies have shown that CAM can be useful for the management of the disease. Although the pathological cause of Alzheimer's disease has not been fully understood, the deposition of beta-amyloid is believed to be one of the risk factors. Therefore, neurotoxicity induced by beta-amyloid is commonly used as a cellular or animal model of Alzheimer's disease. In this issue, an animal study showed that oral administration of Yi-Chi-Tsung-Ming-Tang (Table 1) ameliorated beta-amyloid injection-induced learning and memory impairments. Further investigation by biochemical analysis showed that the herbal decoction decreased amyloid accumulation and reversed acetylcholine decline in the hippocampus of the animals treated with beta-amyloid. Table 1 Composition of herbal formulae. There are two studies on cellular model of Alzheimer's disease with Flemingia macrophylla and Uncaria rhynchophylla, respectively. Beneficial effects of both medical herbs have been suggested for the management of Alzheimer's disease. By using bioassay-guided fractionation, rhynchophylline and isorhynchophylline have been identified as the active ingredients of Uncaria rhynchophylla. The neuroprotective effect of these chemical ingredients has been suggested to be mediated by inhibiting intracellular calcium overloading and tau protein hyperphosphorylation. Depression is a chronic mental disorder clinically characterized by a pervasive low mood, loss of interest or pleasure in daily activities, low self-esteem, and a high suicidal tendency. Although the monoamine theory of depression has been extensively investigated, it is unable to fully explain the pathophysiology of depression. In recent years, a huge amount of evidences suggesting a causal relationship between the incidence of major depressive disorders and neurodegenerative processes such as the decreased neurotrophic factors, altered neuronal plasticity, neuronal atrophy, or destruction in the hippocampus and cortex has been published. At present, there are several types of antidepressants available for pharmaceutical management of the disease including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, noradrenergic reuptake inhibitors, serotonin, and noradrenaline reuptake inhibitors. However, due to the multiple pathogenic factors involved in depression, many antidepressant drugs show low response rates and may cause adverse side effects such as cardiotoxicity, hypertensive crisis, sexual dysfunction, and sleep disorder. Therefore, a number of herbal remedies have been suggested to be safe, better tolerated, and efficacious antidepressants. In this issue, several research articles have shown that herbal prescriptions, including Shu-Yu-San, Kai-Xin-San, Baihe-Dihuang-Tang, and Danggui-Shaoyao-San (Table 1), are effective antidepressants on animal model of depression. In this special issue, we have collected a couple of clinical studies on the application of CAM in treating neurodegenerative diseases. Although the scale of these studies is small, all of them have demonstrated a promising effect of CAM on neurodegenerative diseases. For example, a study of Toki-Shakuyaku-San (Danggui- Shaoyao-San in Chinese phonetic name), a six-herb Chinese medicine (Table 1), on patients with mild cognitive impairment and Alzheimer's disease showed that treatment with Toki-Shakuyaku-San for eight weeks significantly increased regional cerebral blood flow in the posterior cingulate and tended to improve cognitive impairment in these patients. Another randomized clinical trial showed that Saffron (flower of Crocus sativus) supplement improved retinal flicker sensitivity in patients with early age-related macular degeneration and the beneficial effect of the herbal drug was extended over a 14-month follow-up study. In this special issue, a large amount of evidences have shown that CAM can be an efficacious treatment for neurodegenerative disorders. However, a large-scale, double-blind, and placebo-controlled trial is still needed to demonstrate the clinical effect of CAM on these diseases.

Alzheimer's disease (AD) is the most common form of dementia. It is characterized by beta-amyloid (Aβ) peptide fibrils, which are extracellular depositions of a specific protein, and is accompanied by extensive neuroinflammation. Various studies have demonstrated risk factors that can affect AD pathogenesis, and they include accumulation of Aβ, hyperphosphorylation of tau protein, and neuroinflammation. Among these detrimental factors, neuroinflammation has been highlighted by epidemiologic studies suggesting that use of anti-inflammatory drugs could significantly reduce the incidence of AD. Evidence suggests that astrocytes, microglia, and infiltrating immune cells from periphery might contribute to or modify the process of neuroinflammation and neurodegeneration in AD brains. In addition, recent data indicate that microRNAs may affect neuroinflammatory responses in the brain. This article focuses on supportive evidence that neuroinflammation plays a critical role in AD development. In addition, we depict putative therapeutic capacity of anti-inflammatory drugs for AD prevention or treatment. We also discuss pathogenic mechanisms by which astrocytes, microglia, T cells and microRNA participate in AD and the neuroprotective mechanisms of anti-inflammatory drugs.

Alzheimer's disease (AD) is a neurodegenerative disorder that causes memory loss and dementia and is characterized by a decline in cognitive functions. Brain infections, especially induced by herpes simplex virus type-1 (HSV-1), are suggested to play a key role in the pathogenesis of AD. Within the scope of this study, two different AD models (Tau model and amyloid beta [Aβ]) were created in the SH-SY5Y cell line, and HSV glycoprotein B (gB) was applied to the cell line and on the generated AD models. Study groups (n = 3) were designed as (1) control, (2) HSV-gB group, (3) retinoic acid (RA) and brain derived neurotrophic factor (BDNF) induced Alzheimer's model (AD), (4) RA and BDNF induced Alzheimer's model + HSV-gB (ADH), (5) Aβ 1-42 peptide-induced Alzheimer's model (Aβ), and (6) Aβ 1-42 peptide-induced Alzheimer's model + HSV-gB (AβH). Levels of complement proteins and cytokines were determined comparatively. In addition, specific markers of AD (hyperphosphorylated Tau proteins, Aβ 1-40 peptide and amyloid precursor protein) were measured in all groups. HSV-gB administration was found to increase Aβ and hyperphosphorylated Tau levels, similar to AD models. In addition, our data confirmed that the immune system and chronic inflammation might have a crucial role in AD development and that HSV-1 infection might also be an underlying factor of AD.

A relationship between poor oral health conditions and cognitive decline has been clinically observed. A bidirectional association between periodontitis and Alzheimer's disease has been repeatedly identified in clinical and pre-clinical studies. This association is supported by four major overlapped pathways and mechanisms, including the microbiota-gut-brain axis via the vagus nerve pathway, periodontopathogen-involved neuroinflammation via the trigeminal nerve pathway, proinflammatory cytokines, and trained immunity. Partly linked with periodontitis, increased levels of proinflammatory cytokines and decreased levels of anti-inflammatory cytokines can exacerbate the abnormal accumulation of amyloid beta plaques and hyperphosphorylation of tau protein. Periodontitis is considered an important environmental factor involved in Alzheimer's disease development. This review discusses the bidirectional relationship between Alzheimer's disease and periodontitis, focusing on the association between cognitive decline and poor oral health conditions. Thus, oral health intervention strategies have been proposed as potential therapeutic methods for the prevention and management of Alzheimer's disease. [ Psychiatr Ann . 2024;54(8):e230–e234.]

Alzheimer disease (AD) is characterized by neurodegeneration marked by loss of synapses and spines associated with hyperphosphorylation of tau protein. Accumulating amyloid β peptide (Aβ) in brain is linked to neurofibrillary tangles composed of hyperphosphorylated tau in AD. Here, we identify β2-adrenergic receptor (β2AR) that mediates Aβ-induced tau pathology. In the prefrontal cortex (PFC) of 1-year-old transgenic mice with human familial mutant genes of presenilin 1 and amyloid precursor protein (PS1/APP), the phosphorylation of tau at Ser-214 Ser-262 and Thr-181, and the protein kinases including JNK, GSK3α/β, and Ca(2+)/calmodulin-dependent protein kinase II is increased significantly. Deletion of the β2AR gene in PS1/APP mice greatly decreases the phosphorylation of these proteins. Further analysis reveals that in primary PFC neurons, Aβ signals through a β2AR-PKA-JNK pathway, which is responsible for most of the phosphorylation of tau at Ser-214 and Ser-262 and a significant portion of phosphorylation at Thr-181. Aβ also induces a β2AR-dependent arrestin-ERK1/2 activity that does not participate in phosphorylation of tau. However, inhibition of the activity of MEK, an upstream enzyme of ERK1/2, partially blocks Aβ-induced tau phosphorylation at Thr-181. The density of dendritic spines and synapses is decreased in the deep layer of the PFC of 1-year-old PS1/APP mice, and the mice exhibit impairment of learning and memory in a novel object recognition paradigm. Deletion of the β2AR gene ameliorates pathological effects in these senile PS1/APP mice. The study indicates that β2AR may represent a potential therapeutic target for preventing the development of AD.

Alzheimer's disease is a neurodegenerative disorder characterized by cognitive dysfunction and behavioral abnormalities. Neuroinflammatory plaques formed through the extracellular deposition of amyloid-β proteins, as well as neurofibrillary tangles formed by the intracellular deposition of hyperphosphorylated tau proteins, comprise two typical pathological features of Alzheimer's disease. Besides symptomatic treatment, there are no effective therapies for delaying Alzheimer's disease progression. MicroRNAs (miR) are small, non-coding RNAs that negatively regulate gene expression at the transcriptional and translational levels and play important roles in multiple physiological and pathological processes. Indeed, miR-146a, a NF-κB-regulated gene, has been extensively implicated in the development of Alzheimer's disease through several pathways. Research has demonstrated substantial dysregulation of miR-146a both during the initial phases and throughout the progression of this disorder. MiR-146a is believed to reduce amyloid-β deposition and tau protein hyperphosphorylation through the TLR/IRAK1/TRAF6 pathway; however, there is also evidence supporting that it can promote these processes through many other pathways, thus exacerbating the pathological manifestations of Alzheimer's disease. It has been widely reported that miR-146a mediates synaptic dysfunction, mitochondrial dysfunction, and neuronal death by targeting mRNAs encoding synaptic-related proteins, mitochondrial-related proteins, and membrane proteins, as well as other mRNAs. Regarding the impact on glial cells, miR-146a also exhibits differential effects. On one hand, it causes widespread and sustained inflammation through certain pathways, while on the other hand, it can reverse the polarization of astrocytes and microglia, alleviate neuroinflammation, and promote oligodendrocyte progenitor cell differentiation, thus maintaining the normal function of the myelin sheath and exerting a protective effect on neurons. In this review, we provide a comprehensive analysis of the involvement of miR-146a in the pathogenesis of Alzheimer's disease. We aim to elucidate the relationship between miR-146a and the key pathological manifestations of Alzheimer's disease, such as amyloid-β deposition, tau protein hyperphosphorylation, neuronal death, mitochondrial dysfunction, synaptic dysfunction, and glial cell dysfunction, as well as summarize recent relevant studies that have highlighted the potential of miR-146a as a clinical diagnostic marker and therapeutic target for Alzheimer's disease.

Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

Olfactory proteotyping: towards the enlightenment of the neurodegeneration

The amplification of CNS damage in Alzheimer's disease due to SARS-CoV2 infection

Alzheimer’s disease (AD) is the most common age-related, progressive neurodegenerative disease. It is characterized by memory loss and cognitive decline and responsible for most cases of dementia in the elderly. Late-onset or sporadic AD accounts for > 95% of cases, with age at onset > 65 years. Currently there are no drugs or other therapeutic agents available to prevent or delay the progression of AD. The cellular and molecular changes occurring in the brains of individuals with AD include accumulation of β-amyloid peptide and hyperphosphorylated tau protein, decrease of acetylcholine neurotransmitter, inflammation, and oxidative stress. Aggregation of β-amyloid peptide in extracellular plaques and the hyperphosphorylated tau protein in intracellular neurofibrillary tangles are characteristic of AD. A major challenge is identifying molecular biomarkers of the early-stage AD in patients as most studies have been performed with blood or brain tissue samples (postmortem) at late-stage AD. Subjects with mild cognitive impairment almost always have the neuropathologic features of AD with about 50% of mild cognitive impairment patients progressing to AD. They could provide important information about AD pathomechanism and potentially also highlight minimally or noninvasive, easy-to-access biomarkers. MicroRNAs are dysregulated in AD, and may facilitate the early detection of the disease and potentially the continual monitoring of disease progression and allow therapeutic interventions to be evaluated. Four recent reviews have been published of microRNAs in AD, each of which identified areas of weakness or limitations in the reported studies. Importantly, studies in the last three years have shown considerable progress in overcoming some of these limitations and identifying specific microRNAs as biomarkers for AD and mild cognitive impairment. Further large-scale human studies are warranted with less disparity in the study populations, and using an appropriate method to validate the findings.

Recent Advances from the Bench Toward the Bedside in Alzheimer's Disease

This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer’s disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aβ), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis. The AD susceptibility genes apolipoprotein E (APOE), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1) and clusterin (CLU) are involved in the HSV lifecycle. Polymorphisms in these genes may affect brain susceptibility to HSV-1 infection. APOE, for example, influences susceptibility to certain viral infections, HSV-1 viral load in the brain, and the innate immune response. The AD susceptibility gene cholesterol 25-hydroxylase (CH25H) is upregulated in the AD brain and is involved in the antiviral immune response. HSV-1 interacts with additional genes to affect cognition-related pathways and key enzymes involved in Aβ production, Aβ clearance, and hyperphosphorylation of tau proteins. Aβ itself functions as an antimicrobial peptide (AMP) against various pathogens including HSV-1. Evidence is presented supporting the hypothesis that Aβ is produced as an AMP in response to HSV-1 and other brain infections, leading to Aβ deposition and plaque formation in AD. Epidemiologic studies associating HSV-1 infection with AD and cognitive impairment are discussed. Studies are reviewed supporting subclinical chronic reactivation of latent HSV-1 in the brain as significant in the pathogenesis of AD. Finally, the rationale for and importance of clinical trials treating HSV-1-infected MCI and AD patients with antiviral medication is discussed.

Expression of Human Apolipoprotein E4 in Neurons Causes Hyperphosphorylation of Protein Tau in the Brains of Transgenic Mice

Tau Pathology Generated by Overexpression of Tau

Aberrant mitosis occurs in many tauopathy-related neurodegenerative diseases and is believed to precede the formation of neurofibrillary tangles. In this study, we report for the first time that transient cerebral ischemia induces aberrant mitotic proteins and hyperphosphorylation of tau protein with neurofibrillary tangle-like conformational epitopes in adult female rat cortex. Following transient cerebral ischemia in rats, initiation of apoptosis precedes and is potentially integrated with subsequent aberrant mitosis and tau hyperphosphorylation. Furthermore, inhibition of mitosis-related cyclin-dependent kinases (Cdks) by roscovitine significantly reduced the hyperphosphorylation of tau. Administration of the female sex steroid and potent neuroprotective agent, 17beta-estradiol, reduced ischemia-reperfusion-induced cerebral damage and the subsequent aberrant mitosis and tauopathies. These results provide a neuropathological basis for the higher prevalence of dementia in stroke patients and support the hypothesis that apoptosis and aberrant mitosis are integrated pathological events in neurons that may play a critical role in the development of Alzheimer's disease and other tauopathy-related neuropathology.