Current Alzheimer Research - Volume 19, Issue 7, 2022

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by extracellular β-amyloid (Aβ) plaques and cognitive impairments. D-Serine, produced by the enzyme serine racemase (SR) in the brain, functions as an endogenous co-agonist at the glycine-binding site of N-methyl-D-aspartate receptor (NMDAR), has been implicated in the pathophysiological progression of AD. Objectives: Evidence regarding the understanding of the role and dynamic modulation of D-serine during AD progression remains controversial. This literature review aims to offer novel research directions for studying the functions and metabolisms of D-serine in AD brains. Methods: We searched PubMed, using D-serine/SR and AD as keywords. Studies related to NMDAR dysfunction, neuronal excitotoxicity, D-serine dynamic changes and inflammatory response were included. Results: This review primarily discusses: (i) Aβ oligomers’ role in NMDAR dysregulation, and the subsequent synaptic dysfunction and neuronal damage in AD, (ii) D-serine’s role in NMDAR-elicited excitotoxicity, and (iii) the involvement of D-serine and SR in AD-related inflammatory pathological progression. Conclusion: We also presented supposed metabolism and dynamic changes of D-serine during AD progression and hypothesized that: (i) the possible modulation of D-serine levels or SR expression as an effective method of alleviating neurotoxicity during AD pathophysiological progression, and (ii) the dynamic changes of D-serine levels in AD brains possibly resulting from complex processes.

Aging is an inevitable process characterized by progressive loss of physiological integrity and increased susceptibility to cancer, diabetes, cardiovascular, and neurodegenerative diseases; aging is the primary risk factor for Alzheimer’s disease (AD), the most common cause of dementia. AD is characterized by brain pathology, including extracellular deposition of amyloid aggregation and intracellular accumulation of neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition, losses of synapses and a wide range of neurons are pivotal pathologies in the AD brain. Accumulating evidence demonstrates hypoactivation of hippocampal neural networks in the aging brain, whereas AD-related mild cognitive impairment (AD-MCI) begins with hyperactivation, followed by a diminution of hippocampal activity as AD develops. The biphasic trends of the activity of the hippocampal neural network are consistent with the alteration of N-methyl-D-aspartate receptor (NMDA-R) activity from aging to prodromal (AD-MCI) to mid-/late stage AD. D-serine, a product of racemization catalyzed by serine racemase (SR), is an important co-agonist of the NMDA-R which is involved in synaptic events including neurotransmission, synaptogenesis, long-term potentiation (LTP), development, and excitotoxicity. SR and D-serine are decreased in the hippocampus of the aging brain, correlating with impairment of cognitive function. By contrast, SR is increased in AD brain, which is associated with a greater degree of cognitive dysfunction. Emerging studies suggest that D-serine levels in the brain or in cerebral spinal fluid from AD patients are higher than in age-matched controls, but the results are inconsistent. Very recently, serum D-serine levels in AD were reported to correlate with sex and clinical dementia rating (CDR) stage. This review will discuss alterations of NMDA-R and SR in aging and AD brain, and the mechanisms underlying the differential regulation of SR will be probed. Collectively, we propose that SR may be a molecular switch that distinguishes the effects of aging from those of AD on the brain.

Background: Early-onset Semantic dementia (EOSD) and early-onset Alzheimer's disease (EOAD) are often difficult to clinically differentiate in the early stages of the diseases because of the overlaps of clinical symptoms such as language symptoms. We compared the degree of atrophy in medial temporal structures between the two types of dementia using the voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD). Methods: The participants included 29 (age: 61.7±4.5 years) and 39 (age: 60.2±4.9 years) patients with EOSD and EOAD, respectively. The degree of atrophy in medial temporal structures was quantified using the VSRAD for magnetic resonance imaging data. Receiver operating characteristic (ROC) analysis was performed to distinguish patients with EOSD and EOAD using the mean Z score (Z-score) in bilateral medial temporal structures and the absolute value (laterality score) of the laterality of Z-score (| right–left |) for indicating the degree of asymmetrical atrophy in medial temporal structures. Results: The EOSD group had significantly higher Z and laterality scores than the EOAD group (Zscores: mean ± standard deviation: 3.74±1.05 vs. 1.56±0.81, respectively; P<0.001; laterality score: mean ± standard deviation: 2.35±1.23 vs. 0.68±0.51, respectively; P<0.001). In ROC analysis, the sensitivity and specificity to differentiate EOSD from EOAD by a Z-score of 2.29 were 97% and 85%, respectively and by the laterality score of 1.05 were 93% and 85%, respectively. Conclusion: EOSD leads to more severe and asymmetrical atrophy in medial temporal structures than EOAD. The VSRAD may be useful to distinguish between these dementias that have several clinically similar symptoms.

Background: Neurodegenerative diseases, such as Alzheimer's disease patients (AD), Huntington's disease (HD) and Parkinson’s disease (PD), are common causes of morbidity, mortality, and cognitive impairment in older adults. Objective: We aimed to understand the transcriptome characteristics of the cortex of neurodegenerative diseases and to provide an insight into the target genes of differently expressed microRNAs in the occurrence and development of neurodegenerative diseases. Methods: The Limma package of R software was used to analyze GSE33000, GSE157239, GSE64977 and GSE72962 datasets to identify the differentially expressed genes (DEGs) and microRNAs in the cortex of neurodegenerative diseases. Bioinformatics methods, such as GO enrichment analysis, KEGG enrichment analysis and gene interaction network analysis, were used to explore the biological functions of DEGs. Weighted gene co-expression network analysis (WGCNA) was used to cluster DEGs into modules. RNA22, miRDB, miRNet 2.0 and TargetScan7 databases were performed to predict the target genes of microRNAs. Results: Among 310 Alzheimer's disease (AD) patients, 157 Huntington's disease (HD) patients and 157 non-demented control (Con) individuals, 214 co-DEGs were identified. Those co-DEGs were filtered into 2 different interaction network complexes, representing immune-related genes and synapserelated genes. The WGCNA results identified five modules: yellow, blue, green, turquoise, and brown. Most of the co-DEGs were clustered into the turquoise module and blue module, which respectively regulated synapse-related function and immune-related function. In addition, human microRNA-4433 (hsa-miR-4443), which targets 18 co-DEGs, was the only 1 co-up-regulated microRNA identified in the cortex of neurodegenerative diseases. Conclusion: 214 DEGs and 5 modules regulate the immune-related and synapse-related function of the cortex in neurodegenerative diseases. Hsa-miR-4443 targets 18 co-DEGs and may be a potential molecular mechanism in neurodegenerative diseases' occurrence and development.

Background/Objective: AD-associated PSEN1 mutations exhibit high clinical heterogeneity. The discovery of these mutations and the analysis of their associations with cases such as EOAD should be critical to understanding AD's pathogenesis. Methods: We performed clinical analysis, neuroimaging, target region capture and high-throughput sequencing, and Sanger sequencing in a family of 3 generations. The underlying Alzheimer’s pathology was evaluated using biomarker evidence obtained from cerebrospinal fluid (CSF) amyloid testing and ¹⁸F-florbetapir (AV-45) PET imaging. Results: Target region capture sequencing revealed a novel heterozygous C to T missense point mutation at the base position 284 (c.850 C>T) located in exon 8 of the PSEN1 gene, resulting in a Prolineto- Serine substitution (P284S) at codon position 850. The mutation was also identified by Sanger sequencing in 2 family members, including proband and her daughter and was absent in the other 4 unaffected family members and 50 control subjects. Cerebrospinal fluid (CSF) amyloid test exhibited biomarker evidence of underlying Alzheimer’s pathology. ¹⁸F-florbetapir (AV-45) PET imaging indicated extensive cerebral cortex and cerebellar Aβ deposition. Conclusions: We discovered a novel PSEN1 pathogenic mutation, P284S, observed for the first time in a Chinese family with early-onset AD.

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and ApoE4 variants are significant risk factors for AD. Epigenetic modifications are involved in AD pathology. However, it is unclear whether DNA/RNA methylation plays a role in AD pathology, and dysregulation of DNA/RNA methylation occurs in ApoE4 carriers. Objective: The present study aimed to determine whether dysregulation of DNA/RNA methylation is present in the brains of ApoE4 carriers and AD patients. Methods: In this study, postmortem brain tissues from carriers of ApoE4 and ApoE3, from AD and non- AD controls, were used in the analysis of DNA/RNA methylation, methyltransferases, and their demethylases. Results: Immunofluorescence staining indicates that RNA methylation is suppressed in ApoE4 carriers. Further analysis shows that the expression of RNA methyltransferases and an RNA methylation reader is suppressed in ApoE4 carriers, whereas RNA demethylase expression is increased. RNA hypomethylation occurs in NeuN+ neurons in ApoE4 carriers and AD patients. Furthermore, in ApoE4 carriers, both DNA methyltransferases and demethylases are downregulated, and overall DNA methylation levels are unchanged. Conclusion: Our finding indicates that RNA methylation decreased in ApoE4 carriers before AD pathology and AD individuals. The expression of RNA methyltransferases and RNA methylation reader is inhibited, and RNA demethylase is upregulated in ApoE4 carriers, which leads to suppression of RNA methylation, and the suppression precedes the AD pathogenesis and persists through AD pathology.

Background: Rivastigmine, a reversible AChEI for symptomatic treatment of mild to moderately severe Alzheimer’s dementia, is administered once daily transdermal patches, enabling an easier and continuous drug delivery. A novel multi-day (twice week) patch formulation was developed with greater convenience for patients’ therapeutic management. Objective: To assess the bioequivalence under SS conditions of the multiple-day rivastigmine transdermal patch (Test Product, RID-TDS) in comparison to the once-daily Exelon® transdermal patch (Reference Product), both at a release rate of 9.5 mg/24 h. Design: Single-center, open-label, randomized, multiple-dose study in healthy male adults in a 2- period, 2-sequence-crossover design with multiple applications. Methods: Patches were applied on 11 consecutive days for Exelon® and a 4-3-4-day regimen for the multiday test patch (RID-TDS), separated by a 14-day wash-out period. The safety, local tolerability and inhibitory effect of rivastigmine on plasma BuChE activity were also evaluated. Results: 57 subjects completed the study according to the protocol. Calculated point estimates and 90% CI for all primary parameters (AUC96-264, Cmax96-264 and Cmin96-264) were within the predefined acceptance interval of 80.00-125.00%. They were 113.64% (107.33-120.33), 105.14% (98.38- 112.38) and 107.82% (97.78-118.89) respectively. Satisfactory adhesion (CI of mean adhesion above 90%) was demonstrated for RID-TDS but not for Exelon®. Conclusion: Bioequivalence was demonstrated between RID-TDS mg twice a week and Exelon® once daily in SS. Patch adhesion favored RID-TDS despite the longer dosing interval. Both products were well tolerated.