The circRNA and Role in Alzheimer’s Disease: From Regulation to Therapeutic and Diagnostic Targets

Alzheimer\'s disease (AD) is a devastating neurodegenerative disorder and the most common form of dementia worldwide. Although the great progress on the prevention and treatment of AD, no effective therapies are available as yet. With the increasing incidence of AD, it has brought a growing burden to the family and society. Histopathologically, AD is characterized by the presence of myloid β (Aβ) plaques composed of Aβ and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau proteins, which lead to neuronal loss. However, the full spectrum of precise molecular mechanism that contribute to AD pathogenesis remains largely unknown. circular RNAs (circRNAs) are a novel class of endogenous non-coding RNAs that play a vital role in post-transcriptional regulation. Recent reports showed circRNAs to be an important player in the development of neurodegenerative diseases like AD. In this chapter, we review recent progress on understanding the role of circRNAs in AD, and many studies implicating specific circRNAs in the development of the disease. Moreover, we explore the potential promise of these findings for future diagnosis and treatment.

PINK1 Alleviates Cognitive Impairments via Attenuating Pathological Tau Aggregation in a Mouse Model of Tauopathy

As a primary cause of dementia and death in older people, Alzheimer’s disease (AD) has become a common problem and challenge worldwide. Abnormal accumulation of tau proteins in the brain is a hallmark pathology of AD and is closely related to the clinical progression and severity of cognitive deficits. Here, we found that overexpression of phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) effectively promoted the degradation of tau, thereby rescuing neuron loss, synaptic damage, and cognitive impairments in a mouse model of tauopathy with AAV-full-length human Tau (hTau) injected into the hippocampal CA1 area (hTau mice). Overexpression of PINK1 activated autophagy, and chloroquine but not MG132 reversed the PINK1-induced decrease in human Tau levels and cognitive improvement in hTau mice. Furthermore, PINK1 also ameliorated mitochondrial dysfunction induced by hTau. Taken together, our data revealed that PINK1 overexpression promoted degradation of abnormal accumulated tau via the autophagy–lysosome pathway, indicating that PINK1 may be a potential target for AD treatment.

Case Report: Semantic Variant of Primary Progressive Aphasia Associated With Anti-Glial Fibrillary Acid Protein Autoantibodies

BackgroundFrontotemporal lobar degeneration is a heterogeneous disorder entailing a semantic variant of primary progressive aphasia (svPPA). A subtype of frontotemporal dementia associated with glutamate receptor subunit 3 (GluA3) antibody of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was recently identified. Here, we describe the novelty of a svPPA associated with anti-glial fibrillary acid protein (GFAP) antibodies.MethodsTo diagnose this 68-year-old woman we conducted a clinical examination, neuropsychological testing, CSF analysis, MRI and 18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET)/computed tomography (CT) imaging.ResultsThe clinical phenotype corresponds to a svPPA based on impaired confrontation naming and single-word comprehension. In addition, we observed spared speech production, impaired object knowledge, and surface dyslexia - further supporting the diagnosis of svPPA. Additional characteristic imaging features such as anterior temporal hypometabolism in 18F-FDG PET/CT confirmed patient’s svPPA diagnosis. CSF analysis revealed signs of axonal degeneration, as both tau and phosphorylated tau proteins exceeded normal levels. Her serum showed anti-GFAP autoantibodies.ConclusionWe diagnosed a svPPA in this patient and report an association between serum anti-GFAP antibodies and svPPA never reported in the literature so far, thereby expanding the clinical spectrum of svPPA and anti-GFAP-antibody related disease. Further research is needed to elucidate the underlying immunopathology of this disease entity to ultimately improve treatment.

Strategic Modification of Gut Microbiota through Oral Bacteriotherapy Influences Hypoxia Inducible Factor-1α: Therapeutic Implication in Alzheimer’s Disease

Dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis, and oral bacteriotherapy represents a promising preventative and therapeutic opportunity to remodel gut microbiota and to delay AD onset and progression by reducing neuroinflammation and amyloid and tau proteins aggregation. Specifically, SLAB51 multi-strain probiotic formulation positively influences multiple neuro-chemical pathways, but exact links between probiotics oral consumption and cerebral beneficial effects remain a gap of knowledge. Considering that cerebral blood oxygenation is particularly reduced in AD and that the decreased neurovascular function contributes to AD damages, hypoxia conditioning represents an encouraging strategy to cure diseases of the central nervous system. In this work, 8-week-old 3xTg-AD and wild-type mice were chronically supplemented with SLAB51 to evaluate effects on hypoxia-inducible factor-1α (HIF-1α), a key molecule regulating host-microbial crosstalk and a potential target in neurodegenerative pathologies. We report evidence that chronic supplementation with SLAB51 enhanced cerebral expression of HIF-1α and decreased levels of prolyl hydroxylase 2 (PHD2), an oxygen dependent regulator of HIF-1α degradation; moreover, it successfully counteracted the increase of inducible nitric oxide synthase (iNOS) brain expression and nitric oxide plasma levels in AD mice. Altogether, the results demonstrate an additional mechanism through which SLAB51 exerts neuroprotective and anti-inflammatory effects in this model of AD.

Therapeutic Potential of Ferulic Acid in Alzheimer's Disease

Alzheimer's Disease (AD) is one of the most important neurodegenerative diseases and it covers 60% of whole dementia cases. AD is a constantly progressing neurodegenerative disease as a result of the production of β-amyloid (Aβ) protein and the accumulation of hyper-phosphorylated Tau protein; it causes breakages in the synaptic bonds and neuronal deaths to a large extent. Millions of people worldwide suffer from AD because there is no definitive drug for disease prevention, treatment or slowdown. Over the last decade, multiple target applications have been developed for AD treatments. These targets include Aβ accumulations, hyper-phosphorylated Tau proteins, mitochondrial dysfunction, and oxidative stress resulting in toxicity. Various natural or semisynthetic antioxidant formulations have been shown to protect brain cells from Aβ induced toxicity and provide promising potentials for AD treatment. Ferulic acid (FA), a high-capacity antioxidant molecule, is naturally synthesized from certain plants. FA has been shown to have different substantial biological properties, such as anticancer, antidiabetic, antimicrobial, anti-inflammatory, hepatoprotective, and cardioprotective actions, etc. Furthermore, FA exerted neuroprotection via preventing Aβ-fibril formation, acting as an anti-inflammatory agent, and inhibiting free radical generation and acetylcholinesterase (AChE) enzyme activity. In this review, we present key biological roles of FA and several FA derivatives in Aβ-induced neurotoxicity, protection against free radical attacks, and enzyme inhibitions and describe them as possible therapeutic agents for the treatment of AD.

Biomarkers for Differential Diagnosis Between Chronic Traumatic Encephalopathy and Alzheimer Disease: A Systematic Review

ObjectiveTo assess the diagnostic utility of biomarkers that could differentiate Chronic Traumatic Encephalopathy (CTE) from Alzheimer disease (AD).BackgroundCTE is a neurodegenerative disease associated with multiple head trauma. The diagnosis depends on neuropathologic findings postmortem, and patients can present cognitive and behavioral changes. These symptoms can usually be mistaken for other dementias, such as AD, leading to an underestimated frequency of CTE. Therefore, specific biomarkers can be useful for comprehending disease development, diagnosis and prognosis.Design/MethodsWe systematically searched the MEDLINE, Embase and Cochrane databases. We also searched the trial registries and reference lists of articles. We included studies that were relevant to the PICO question posed and analysed different biomarkers. We screened titles and abstracts and if they were pertinent, we assessed the full text and reported results narratively.ResultsTwenty-two studies were identified through database searching. One study was excluded due to duplicity among the databases. Twenty-one articles were assessed for eligibility and 6 were included in the qualitative synthesis. P-Tau and T-tau proteins were indicated as biomarkers of neurodegenerative diseases such as CTE and AD, but not from other tauopathies. Exosomal tau levels are higher in CTE patients than in AD patients, and it might be useful since it is very stable, crosses the blood–brain barrier and reflects their cellular origin. Pathophysiologic differences between CTE and AD are pointed out as a way to find specific biomarkers for CTE. The biomarkers associated with neuroaxonal damage (NFL), glial response with astroglial scarring (GFAP and sTREM2), and microvascular damage with disruption of the blood–brain barrier (cerebrospinal fluid/serum albumin ratio) are promising in that way.ConclusionsBiomarkers that arise from pathophysiologic processes distinct from the 2 diseases, appear to be promising. However, further well-designed studies are needed to assess the real utility of the biomarkers in differential diagnosis between CTE and AD.

Putative Factors Interfering Cell Cycle Re-Entry in Alzheimer’s Disease: An Omics Study with Differential Expression Meta-Analytics and Co-Expression Profiling

Background: Neuronal cell cycle re-entry (CCR) is a mechanism, along with amyloid-β (Aβ) oligomers and hyperphosphorylated tau proteins, contributing to toxicity in Alzheimer’s disease (AD). Objective: This study aimed to examine the putative factors in CCR based on evidence corroboration by combining meta-analysis and co-expression analysis of omic data. Methods: The differentially expressed genes (DEGs) and CCR-related modules were obtained through the differential analysis and co-expression of transcriptomic data, respectively. Differentially expressed microRNAs (DEmiRNAs) were extracted from the differential miRNA expression studies. The dysregulations of DEGs and DEmiRNAs as binary outcomes were independently analyzed by meta-analysis based on a random-effects model. The CCR-related modules were mapped to human protein-protein interaction databases to construct a network. The importance score of each node within the network was determined by the PageRank algorithm, and nodes that fit the pre-defined criteria were treated as putative CCR-related factors. Results: The meta-analysis identified 18,261 DEGs and 36 DEmiRNAs, including genes in the ubiquitination proteasome system, mitochondrial homeostasis, and CCR, and miRNAs associated with AD pathologies. The co-expression analysis identified 156 CCR-related modules to construct a protein-protein interaction network. Five genes, UBC, ESR1, EGFR, CUL3, and KRAS, were selected as putative CCR-related factors. Their functions suggested that the combined effects of cellular dyshomeostasis and receptors mediating Aβ toxicity from impaired ubiquitination proteasome system are involved in CCR. Conclusion: This study identified five genes as putative factors and revealed the significance of cellular dyshomeostasis in the CCR of AD.

Borrelia burgdorferi Co-Localizing with Amyloid Markers in Alzheimer’s Disease Brain Tissues

Background: Infections by bacterial or viral agents have been hypothesized to influence the etiology of neurodegenerative diseases. Objective: This study examined the potential presence of Borrelia burgdorferi spirochete, the causative agent of Lyme disease, in brain autopsy tissue of patients diagnosed with either Alzheimer’s (AD) or Parkinson’s diseases. Methods: Brain tissue sections from patients with age-matched controls were evaluated for antigen and DNA presence of B. burgdorferi using various methods. Positive Borrelia structures were evaluated for co-localization with biofilm and AD markers such as amyloid and phospho-tau (p-Tau) using immunohistochemical methods. Results: The results showed the presence of B. burgdorferi antigen and DNA in patients with AD pathology and among those, one of them was previously diagnosed with Lyme disease. Interestingly, a significant number of Borrelia-positive aggregates with a known biofilm marker, alginate, were found along with the spirochetal structures. Our immunohistochemical data also showed that Borrelia-positive aggregates co-localized with amyloid and anti-phospho-tau markers. To further prove the potential relationship of B. burgdorferi and amyloids, we infected two mammalian cell lines with B. burgdorferi which resulted in a significant increase in the expression of amyloid-β and p-Tau proteins in both cells lines post-infection. Conclusion: These results indicate that B. burgdorferi can be found in AD brain tissues, not just in spirochete but a known antibiotics resistant biofilm form, and its co-localized amyloid markers. In summary, this study provides evidence for a likely association between B. burgdorferi infections and biofilm formation, AD pathology, and chronic neurodegenerative diseases.

Symmetric and Asymmetric Synapses Driving Neurodegenerative Disorders

In 1959, E. G. Gray described two different types of synapses in the brain for the first time: symmetric and asymmetric. Later on, symmetric synapses were associated with inhibitory terminals, and asymmetric synapses to excitatory signaling. The balance between these two systems is critical to maintain a correct brain function. Likewise, the modulation of both types of synapses is also important to maintain a healthy equilibrium. Cerebral circuitry responds differently depending on the type of damage and the timeline of the injury. For example, promoting symmetric signaling following ischemic damage is beneficial only during the acute phase; afterwards, it further increases the initial damage. Synapses can be also altered by players not directly related to them; the chronic and long-term neurodegeneration mediated by tau proteins primarily targets asymmetric synapses by decreasing neuronal plasticity and functionality. Dopamine represents the main modulating system within the central nervous system. Indeed, the death of midbrain dopaminergic neurons impairs locomotion, underlying the devastating Parkinson’s disease. Herein, we will review studies on symmetric and asymmetric synapses plasticity after three different stressors: symmetric signaling under acute damage—ischemic stroke; asymmetric signaling under chronic and long-term neurodegeneration—Alzheimer’s disease; symmetric and asymmetric synapses without modulation—Parkinson’s disease.

STMO-5 Utilization of intraoperative multimodal technologies [PET and 5-ALA] for treating glioblastoma

Background: We can improve prognosis of glioblastoma by using positron emission tomography (PET) scans to guide them in removing tumors, and intraoperative magnetic resonance imaging (IoMRI) and 5-aminolevulinic acid (5-ALA) for identifying residual tumors. Tau proteins are reported to accumulate in glioblastomas, so we compared the efficacy of their PET tracer, THK5351, against that of 11C-MET, 18F-FLT, and 18F-FMISO. Methods: Patients (n = 11) underwent scans between February 2020 and July 2021 for glioblastoma resection. Tumor-to-normal tissue accumulation ratio (TNR) and accumulation volumes of 4 PET tracers were evaluated. Following excisions, 5-ALA fluorescent evaluation was classified as strong, vague, or none. Residual tumor volumes and removal rates were determined using T1Gd assessments and PET tracers. IoMRI confirmed presence of residual tumors.Results: THK5351 had a TNR of 5.20, and its accumulated volume was greater than that of other tracers: 1.80 for 11C-MET, 1.72 for 18F-FLT, and 2.82 for 18F-FMISO. 5-ALA fluorescent evaluation was vague (n = 7) or none (n = 4); respective residual tumor volumes (mL) were 2.3 and 0.2 (T1Gd), 5.7 and 0.9 (11C-MET), 5.6 and 0.6 (18F-FLT), 1.3 and 0.4 (18F-FMISO), and 7 and 1.4 (THK5351); respective tumor removal rates (%) were 90.4 and 99.6 (T1Gd), 79.2 and 86.4 (11C-MET), 84.4 and 89.2 (18F-FLT), 94.3 and 94.4 (18F-FMISO), and 72.3 and 83.4 (THK5351). The excised tumor tissue was found in the area where only THK5351 was accumulated.Conclusions: THK5351 accumulated in glioblastomas to a greater degree than that of other tracers, making it useful for discriminating between healthy and malignant tissues.