BACE1 and Other Alzheimer’s-Related Biomarkers in Cerebrospinal Fluid and Plasma Distinguish Alzheimer’s Disease Patients from Cognitively-Impaired Neurosyphilis Patients

Background: Patients with spirochetal infection, which causes neurosyphilis (NS) and at a later stage general paresis of the insane (GPI), present with brain pathology features of Alzheimer’s disease (AD). However, the relationships among these illnesses regarding biomarker levels are still unclear. Objective: To explore biomarker levels in NS and GPI compared with those in AD and the relationship between biomarker levels and cognitive function in NS and GPI. Methods: Levels of neurogranin (NGRN) and β-amyloid precursor protein cleaving enzyme (BACE1) in cerebrospinal fluid (CSF)/plasma, together with amyloid-β 1–40 (Aβ40), Aβ42, and total tau in the CSF of 23 AD patients, 55 GPI patients, and 13 NS patients were measured. Patients were classified into none-to-mild, moderate, and severe stages of cognitive impairment. Results: Levels of CSF NGRN, BACE1, and tau as well as plasma BACE1 levels were significantly different among groups. In the none-to-mild stage, plasma BACE1 levels correlated with the protein levels in CSF and were significantly increased in AD patients versus GPI patients. The CSF tau levels in AD patients were significantly increased versus GPI patients in the moderate and severe stages. Pooling data from GPI and NS patients, both CSF tau and plasma NGRN levels correlated with cognitive scale scores. Conclusion: GPI and NS patients might have different biomarker level patterns compared to AD patients. While plasma BACE1 could be a promising early biomarker for distinguishing AD from GPI, CSF tau and plasma NGRN levels might be valuable in indications of cognitive function in pooled NS populations.

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MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

Current Neurovascular Research ◽

10.2174/1567202617666200128141938 ◽

2020 ◽

Vol 17 (1) ◽

pp. 93-101 ◽

Cited By ~ 3

Author(s):

Dan Wang ◽

Zhifu Fei ◽

Song Luo ◽

Hai Wang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Western Blot ◽

Mrna Expression ◽

Cognitive Deficits ◽

Protein Levels ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

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Effects of Cholinesterase Inhibitors on the Activities and Protein Levels of Cholinesterases in the Cerebrospinal Fluid of Patients with Alzheimer's disease: A Review of Recent Clinical Studies

Current Alzheimer Research ◽

10.2174/1567209198607252050 ◽

2009 ◽

Vol 999 (999) ◽

pp. 1-6

Author(s):

Taher Darreh-Shori

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Clinical Studies ◽

Cholinesterase Inhibitors ◽

Protein Levels

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Heterogeneity of Amyloid Binding in Cognitively Impaired Patients Consecutively Recruited from a Memory Clinic: Evaluating the Utility of Quantitative 18F-Flutemetamol PET-CT in Discrimination of Mild Cognitive Impairment from Alzheimer’s Disease and Other Dementias

Journal of Alzheimer s Disease ◽

10.3233/jad-200890 ◽

2020 ◽

pp. 1-14

Author(s):

Yi-Wen Bao ◽

Anson C.M. Chau ◽

Patrick Ka-Chun Chiu ◽

Yat Fung Shea ◽

Joseph S.K. Kwan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Amyloid Β ◽

Standardized Uptake Value ◽

Subjective Cognitive Decline ◽

Cognitively Impaired ◽

Memory Clinic ◽

Pet Ct

Background: With the more widespread use of 18F-radioligand-based amyloid-β (Aβ) PET-CT imaging, we evaluated Aβ binding and the utility of neocortical 18F-Flutemetamol standardized uptake value ratio (SUVR) as a biomarker. Objective: 18F-Flutemetamol SUVR was used to differentiate 1) mild cognitive impairment (MCI) from Alzheimer’s disease (AD), and 2) MCI from other non-AD dementias (OD). Methods: 109 patients consecutively recruited from a University memory clinic underwent clinical evaluation, neuropsychological test, MRI and 18F-Flutemetamol PET-CT. The diagnosis was made by consensus of a panel consisting of 1 neuroradiologist and 2 geriatricians. The final cohort included 13 subjective cognitive decline (SCD), 22 AD, 39 MCI, and 35 OD. Quantitative analysis of 16 region-of-interests made by Cortex ID software (GE Healthcare). Results: The global mean 18F-Flutemetamol SUVR in SCD, MCI, AD, and OD were 0.50 (SD-0.08), 0.53 (SD-0.16), 0.76 (SD-0.10), and 0.56 (SD-0.16), respectively, with SUVR in SCD and MCI and OD being significantly lower than AD. Aβ binding in SCD, MCI, and OD was heterogeneous, being 23%, 38.5%, and 42.9% respectively, as compared to 100% amyloid positivity in AD. Using global SUVR, ROC analysis showed AUC of 0.868 and 0.588 in differentiating MCI from AD and MCI from OD respectively. Conclusion: 18F-Flutemetamol SUVR differentiated MCI from AD with high efficacy (high negative predictive value), but much lower efficacy from OD. The major benefit of the test was to differentiate cognitively impaired patients (either SCD, MCI, or OD) without AD-related-amyloid-pathology from AD in the clinical setting, which was under-emphasized in the current guidelines proposed by Amyloid Imaging Task Force.

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Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives

Brain Sciences ◽

10.3390/brainsci11020215 ◽

2021 ◽

Vol 11 (2) ◽

pp. 215

Author(s):

Donovan A. McGrowder ◽

Fabian Miller ◽

Kurt Vaz ◽

Chukwuemeka Nwokocha ◽

Cameil Wilson-Clarke ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Late Onset ◽

Amyloid Β ◽

Current Evidence ◽

Csf Biomarkers ◽

Diagnostic Efficacy ◽

Neurofilament Light ◽

New Biomarkers

Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by a decline in cognition. Over the last two decades, there has been significant growth in the investigation of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. This review presents current evidence from many clinical neurochemical studies, with findings that attest to the efficacy of existing core CSF biomarkers such as total tau, phosphorylated tau, and amyloid-β (Aβ42), which diagnose Alzheimer’s disease in the early and dementia stages of the disorder. The heterogeneity of the pathophysiology of the late-onset disease warrants the growth of the Alzheimer’s disease CSF biomarker toolbox; more biomarkers showing other aspects of the disease mechanism are needed. This review focuses on new biomarkers that track Alzheimer’s disease pathology, such as those that assess neuronal injury (VILIP-1 and neurofilament light), neuroinflammation (sTREM2, YKL-40, osteopontin, GFAP, progranulin, and MCP-1), synaptic dysfunction (SNAP-25 and GAP-43), vascular dysregulation (hFABP), as well as CSF α-synuclein levels and TDP-43 pathology. Some of these biomarkers are promising candidates as they are specific and predict future rates of cognitive decline. Findings from the combinations of subclasses of new Alzheimer’s disease biomarkers that improve their diagnostic efficacy in detecting associated pathological changes are also presented.

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Superior Frontal Gyrus TOMM40-APOE Locus DNA Methylation in Alzheimer’s Disease

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-201000 ◽

2021 ◽

pp. 1-8

Author(s):

Natalia Bezuch ◽

Steven Bradburn ◽

Andrew C. Robinson ◽

Neil Pendleton ◽

Antony Payton ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Fluid Intelligence ◽

Cpg Island ◽

Amyloid Β ◽

Superior Frontal Gyrus ◽

Protein Levels ◽

Apoe Protein ◽

Apoe Locus

Background: The APOE ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer’s disease (AD). The neighboring TOMM40 gene has also been implicated in AD due to its close proximity to APOE. Objective: Here we tested whether methylation of the TOMM40-APOE locus may influence ApoE protein levels and AD pathology. Methods: DNA methylation levels across the TOMM40-APOE locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for APOE and scored for AD neuropathology. Results: Methylation levels within the TOMM40 CpG island in the promoter or APOE CpG island in Exon 4 did not differ between APOE ɛ4 carriers versus non-carriers. However, APOE ɛ4 carriers had significantly higher methylation the APOE promoter compared with non-carriers. Although DNA methylation at TOMM40, APOE promoter region, or APOE did not differ between AD pathological groups, there was a negative association between TOMM40 methylation and CERAD scores. ApoE protein concentrations did not significantly different between APOE ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels. Conclusion: APOE gene methylation may not be affected by genotype, relate to AD pathology or ApoE protein levels in the superior frontal gyrus, though, DNA methylation at the ApoE promoter differed between genotype. DNA methylation at TOMM40 associated with amyloid-β plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the TOMM40-APOE locus in the brain in controlling ApoE protein levels and AD neuropathology.

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Validation and Clinical Utility of ELISA Methods for Quantification of Amyloid-β Peptides in Cerebrospinal Fluid Specimens from Alzheimer's Disease Studies

Journal of Alzheimer s Disease ◽

10.3233/jad-141686 ◽

2015 ◽

Vol 45 (2) ◽

pp. 527-542 ◽

Cited By ~ 7

Author(s):

D. Richard Lachno ◽

Barbara A. Evert ◽

Kaia Maloney ◽

Brian A. Willis ◽

Jayne A. Talbot ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Clinical Utility ◽

Amyloid Β

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The Trajectory of Cerebrospinal Fluid Growth-Associated Protein 43 in the Alzheimer’s Disease Continuum: A Longitudinal Study

Journal of Alzheimer s Disease ◽

10.3233/jad-215456 ◽

2021 ◽

pp. 1-12

Author(s):

Heng Zhang ◽

Diyang Lyu ◽

Jianping Jia ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Amyloid Β ◽

Dementia Patients ◽

Positron Emission ◽

Potential Biomarker ◽

Synaptic Degeneration ◽

Over Time

Background: Synaptic degeneration has been suggested as an early pathological event that strongly correlates with severity of dementia in Alzheimer’s disease (AD). However, changes in longitudinal cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) as a synaptic biomarker in the AD continuum remain unclear. Objective: To assess the trajectory of CSF GAP-43 with AD progression and its association with other AD hallmarks. Methods: CSF GAP-43 was analyzed in 788 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 246 cognitively normal (CN) individuals, 415 individuals with mild cognitive impairment (MCI), and 127 with AD dementia based on cognitive assessments. The associations between a multimodal classification scheme with amyloid-β (Aβ), tau, and neurodegeneration, and changes in CSF GAP-43 over time were also analyzed. Results: CSF GAP-43 levels were increased at baseline in MCI and dementia patients, and increased significantly over time in the preclinical (Aβ-positive CN), prodromal (Aβ-positive MCI), and dementia (Aβ-positive dementia) stages of AD. Higher levels of CSF GAP-43 were also associated with higher CSF phosphorylated tau (p-tau) and total tau (t-tau), cerebral amyloid deposition and hypometabolism on positron emission tomography, the hippocampus and middle temporal atrophy, and cognitive performance deterioration at baseline and follow-up. Furthermore, CSF GAP-43 may assist in effectively predicting the probability of dementia onset at 2- or 4-year follow-up. Conclusion: CSF GAP-43 can be used as a potential biomarker associated with synaptic degeneration in subjects with AD; it may also be useful for tracking the disease progression and for monitoring the effects of clinical trials.

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Abstract T P160: Influence of Polyunsaturated Fatty Acids on Cognition in Elderly Alzheimer's Disease Patients

Stroke ◽

10.1161/str.46.suppl_1.tp160 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Takashi Yamazaki ◽

Ken Nagata ◽

Daiki Takano ◽

Tetsuya Maeda

Keyword(s):

Alzheimer’S Disease ◽

Blood Pressure ◽

Alzheimer's Disease ◽

Cognitive Function ◽

Mmse Score ◽

Characteristic Curve ◽

Follow Up Study ◽

Cognitive Stability ◽

The Relationship

Background: Many genes and environmental factors linked to Alzheimer’s disease (AD) risk affect lipid metabolism or the cardiovascular system, strongly implicating cerebrovascular and metabolic dysfunction in AD pathogenesis. Although some PUFAs may improve cognitive function in aging individuals, it is still unclear how different PUFAs influence AD neuropathology and cognitive function. Objective: To examine the influence of polyunsaturated fatty acid (PUFA) metabolism on AD-associated cognitive decline, we investigated the relationship between serum PUFA profile and neuropsychological test performance. Methods: Cognitive functioning in patients with probable AD (n = 174, mean age 77.6 years) was examined using the Mini-Mental State Exam (MMSE) and clock drawing test (CDT). Serum samples were obtained for PUFA profile, including the eicosapentaenoic acid/arachidonic acid (EPA/AA) ratio, and measurement of brain natriuretic peptide (BNP) concentration. In the follow-up study, 47 subjects repeated MMSE and CDT after 1 year, According to the second MMSE score, the subjects were divided into the following 2 groups: those with unchanged or improved MMSE score and those with lower MMSE score. A receiver operating characteristic curve was used to evaluate the relationship between the EPA/AA ratio and 1-year cognitive stability. Results: In the cross-sectional study, total MMSE score correlated positively with the EPA/AA ratio and systolic blood pressure (SBP), and negatively with age and diastolic blood pressure (DBP) (p < 0.05). In the follow-up study, the MMSE score was lower than baseline in 20 subjects, whereas it was improved or unchanged in 29 patients. The EPA/AA ratio in the stable group was significantly greater than that in the deteriorating group, suggesting an association between higher EPA/AA ratio and cognitive stability over 1 year. The EPA/AA ratio predicted stability of cognitive performance with a sensitivity of 66% and specificity of 70% (odds ratio = 4.43) when the cut-off was 0.67. Conclusion: Our results suggest that serum EPA concentration strongly influences cognitive performances in AD patients. The EPA/AA ratio was a sensitive indicator of cognitive stability in this patient group.

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MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation

Brain ◽

10.1093/brain/awy305 ◽

2018 ◽

Vol 142 (1) ◽

pp. 176-192 ◽

Cited By ~ 13

Author(s):

Bing-Lin Zhu ◽

Yan Long ◽

Wei Luo ◽

Zhen Yan ◽

Yu-Jie Lai ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

Amyloid Β ◽

Translation Initiation Factor ◽

Precursor Protein ◽

Initiation Factor ◽

Luciferase Reporter ◽

Protein Levels ◽

Model Of Alzheimer’S Disease

AbstractMMP13 (matrix metallopeptidase 13) plays a key role in bone metabolism and cancer development, but has no known functions in Alzheimer’s disease. In this study, we used high-throughput small molecule screening in SH-SY5Y cells that stably expressed a luciferase reporter gene driven by the BACE1 (β-site amyloid precursor protein cleaving enzyme 1) promoter, which included a portion of the 5′ untranslated region (5′UTR). We identified that CL82198, a selective inhibitor of MMP13, decreased BACE1 protein levels in cultured neuronal cells. This effect was dependent on PI3K (phosphatidylinositide 3-kinase) signalling, and was unrelated to BACE1 gene transcription and protein degradation. Further, we found that eukaryotic translation initiation factor 4B (eIF4B) played a key role, as the mutation of eIF4B at serine 422 (S422R) or deletion of the BACE1 5′UTR attenuated MMP13-mediated BACE1 regulation. In APPswe/PS1E9 mice, an animal model of Alzheimer’s disease, hippocampal Mmp13 knockdown or intraperitoneal CL82198 administration reduced BACE1 protein levels and the related amyloid-β precursor protein processing, amyloid-β load and eIF4B phosphorylation, whereas spatial and associative learning and memory performances were improved. Collectively, MMP13 inhibition/CL82198 treatment exhibited therapeutic potential for Alzheimer’s disease, via the translational regulation of BACE1.

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