Green Tea Suppresses Amyloid β Levels and Alleviates Cognitive Impairment by Inhibiting APP Cleavage and Preventing Neurotoxicity in 5XFAD Mice

AbstractFull dynamics of biofluid biomarkers have been unknown in patients with Parkinson’s disease (PD). Using data from 396 PD patients and 182 controls in the Parkinson's Progression Markers Initiative (PPMI) database, we estimated long-term temporal trajectories of CSF α-synuclein (α-syn), amyloid-β (Aβ), total tau (t-tau), phosphorylated tau (p-tau) and serum neurofilament light chain (NfL) by integrating function between the baseline levels and annual changes. At baseline, PD patients showed lower CSF α-syn, Aβ, t-tau and p-tau levels than those of the controls. In all PD patients, CSF α-syn and Aβ decreased in a negative exponential pattern before the onset of motor symptoms, whereas CSF t-tau and p-tau, and serum NfL increased. Patients with cognitive impairment exhibited faster decline of Aβ and α-syn and faster rise of t-tau, p-tau and NfL, when compared to those without. Similarly, low Aβ group showed earlier decline of α-syn, faster rise of t-tau, p-tau and NfL, and faster decline of cognitive performances, when compared to high Aβ group. Our results suggest that longitudinal changes in biomarkers can be influenced by cognitive impairment and Aβ burden at baseline. PD patients with Aβ pathology may be associated with early appearance of α-synuclein pathology, rapid progression of axonal degeneration and neurodegeneration, and consequently greater cognitive decline.

Download Full-text

Impaired spike-gamma coupling of area CA3 fast-spiking interneurons as the earliest functional impairment in the AppNL-G-F mouse model of Alzheimer’s disease

Molecular Psychiatry ◽

10.1038/s41380-021-01257-0 ◽

2021 ◽

Author(s):

Luis Enrique Arroyo-García ◽

Arturo G. Isla ◽

Yuniesky Andrade-Talavera ◽

Hugo Balleza-Tapia ◽

Raúl Loera-Valencia ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mouse Model ◽

Functional Impairment ◽

Amyloid Β ◽

Gamma Oscillations ◽

Gamma Oscillation ◽

Gamma Rhythm ◽

Fast Spiking

AbstractIn Alzheimer’s disease (AD) the accumulation of amyloid-β (Aβ) correlates with degradation of cognition-relevant gamma oscillations. The gamma rhythm relies on proper neuronal spike-gamma coupling, specifically of fast-spiking interneurons (FSN). Here we tested the hypothesis that decrease in gamma power and FSN synchrony precede amyloid plaque deposition and cognitive impairment in AppNL-G-F knock-in mice (AppNL-G-F). The aim of the study was to evaluate the amyloidogenic pathology progression in the novel AppNL-G-F mouse model using in vitro electrophysiological network analysis. Using patch clamp of FSNs and pyramidal cells (PCs) with simultaneous gamma oscillation recordings, we compared the activity of the hippocampal network of wild-type mice (WT) and the AppNL-G-F mice at four disease stages (1, 2, 4, and 6 months of age). We found a severe degradation of gamma oscillation power that is independent of, and precedes Aβ plaque formation, and the cognitive impairment reported previously in this animal model. The degradation correlates with increased Aβ1-42 concentration in the brain. Analysis on the cellular level showed an impaired spike-gamma coupling of FSN from 2 months of age that correlates with the degradation of gamma oscillations. From 6 months of age PC firing becomes desynchronized also, correlating with reports in the literature of robust Aβ plaque pathology and cognitive impairment in the AppNL-G-F mice. This study provides evidence that impaired FSN spike-gamma coupling is one of the earliest functional impairment caused by the amyloidogenic pathology progression likely is the main cause for the degradation of gamma oscillations and consequent cognitive impairment. Our data suggests that therapeutic approaches should be aimed at restoring normal FSN spike-gamma coupling and not just removal of Aβ.

Download Full-text

Region-specific amyloid-β accumulation in the olfactory system influences olfactory sensory neuronal dysfunction in 5xFAD mice

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00730-2 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Gowoon Son ◽

Seung-Jun Yoo ◽

Shinwoo Kang ◽

Ameer Rasheed ◽

Da Hae Jung ◽

...

Keyword(s):

Olfactory Bulb ◽

Sensory Neurons ◽

Olfactory System ◽

Amyloid Β ◽

Olfactory Sensory Neurons ◽

Basal Cells ◽

Irreversible Damage ◽

5Xfad Mouse ◽

Peripheral Areas ◽

5Xfad Mice

Abstract Background Hyposmia in Alzheimer’s disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-β (Aβ), which is one of the toxic factors upregulated early in AD, has been identified in many studies, even in the peripheral areas of the olfactory system, the pathology involving olfactory sensory neurons (OSNs) remains poorly understood. Methods Here, we focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also confirmed histologically the pathological changes in 3-month-old 5xFAD mouse models, which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of the anatomical plane. Results We observed the odorant group that the 5xFAD mice showed reduced responses to odorants. These also did not physiologically activate OSNs that propagate their axons to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-β (Aβ) was high in the OSNs located in the olfactory epithelial ectoturbinate and the ventral olfactory bulb glomeruli. We also observed irreversible damage to the ectoturbinate of the olfactory epithelium by measuring the impaired neuronal turnover ratio from the basal cells to the matured OSNs. Conclusions Our results showed that partial and asymmetrical accumulation of Aβ coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely associated with peripheral OSN’s loss could be a leading cause of AD-related hyposmia, a characteristic of early AD.

Download Full-text

Interleukin-1β mediates alterations in mitochondrial fusion/fission proteins and memory impairment induced by amyloid-β oligomers

Journal of Neuroinflammation ◽

10.1186/s12974-021-02099-x ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Andre F. Batista ◽

Tayná Rody ◽

Leticia Forny-Germano ◽

Suzana Cerdeiro ◽

Maria Bellio ◽

...

Keyword(s):

Cognitive Impairment ◽

Mitochondrial Dysfunction ◽

Memory Impairment ◽

Mitochondrial Dynamics ◽

Interleukin 1 ◽

Amyloid Β ◽

Mitochondrial Fusion ◽

Synapse Loss ◽

Cynomolgus Macaques ◽

The Impact

Abstract Background The lack of effective treatments for Alzheimer’s disease (AD) reflects an incomplete understanding of disease mechanisms. Alterations in proteins involved in mitochondrial dynamics, an essential process for mitochondrial integrity and function, have been reported in AD brains. Impaired mitochondrial dynamics causes mitochondrial dysfunction and has been associated with cognitive impairment in AD. Here, we investigated a possible link between pro-inflammatory interleukin-1 (IL-1), mitochondrial dysfunction, and cognitive impairment in AD models. Methods We exposed primary hippocampal cell cultures to amyloid-β oligomers (AβOs) and carried out AβO infusions into the lateral cerebral ventricle of cynomolgus macaques to assess the impact of AβOs on proteins that regulate mitochondrial dynamics. Where indicated, primary cultures were pre-treated with mitochondrial division inhibitor 1 (mdivi-1), or with anakinra, a recombinant interleukin-1 receptor (IL-1R) antagonist used in the treatment of rheumatoid arthritis. Cognitive impairment was investigated in C57BL/6 mice that received an intracerebroventricular (i.c.v.) infusion of AβOs in the presence or absence of mdivi-1. To assess the role of interleukin-1 beta (IL-1β) in AβO-induced alterations in mitochondrial proteins and memory impairment, interleukin receptor-1 knockout (Il1r1−/−) mice received an i.c.v. infusion of AβOs. Results We report that anakinra prevented AβO-induced alteration in mitochondrial dynamics proteins in primary hippocampal cultures. Altered levels of proteins involved in mitochondrial fusion and fission were observed in the brains of cynomolgus macaques that received i.c.v. infusions of AβOs. The mitochondrial fission inhibitor, mdivi-1, alleviated synapse loss and cognitive impairment induced by AβOs in mice. In addition, AβOs failed to cause alterations in expression of mitochondrial dynamics proteins or memory impairment in Il1r1−/− mice. Conclusion These findings indicate that IL-1β mediates the impact of AβOs on proteins involved in mitochondrial dynamics and that strategies aimed to prevent pathological alterations in those proteins may counteract synapse loss and cognitive impairment in AD.

Download Full-text

Effects of Folic Acid Combined with DHA Supplementation on Cognitive Function and Amyloid-β-Related Biomarkers in Older Adults with Mild Cognitive Impairment by a Randomized, Double Blind, Placebo-Controlled Trial

Journal of Alzheimer s Disease ◽

10.3233/jad-200997 ◽

2021 ◽

pp. 1-13

Author(s):

Dong Bai ◽

Junting Fan ◽

Mengyue Li ◽

Cuixia Dong ◽

Yiming Gao ◽

...

Keyword(s):

Cognitive Impairment ◽

Folic Acid ◽

Mild Cognitive Impairment ◽

Cognitive Function ◽

Digit Span ◽

Controlled Trial ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Double Blind ◽

Full Scale Intelligence Quotient

Background: The neuroprotective benefits of combined folic acid and docosahexaenoic acid (DHA) on cognitive function in mild cognitive impairment (MCI) patients are suggested but unconfirmed. Objective: To explore the effects of 6-month folic acid + DHA on cognitive function in patients with MCI. Methods: Our randomized controlled trial (trial number ChiCTR-IOR-16008351) was conducted in Tianjin, China. We divided 160 MCI patients aged > 60 years into four regimen groups randomly: folic acid (0.8 mg/day) + DHA (800 mg/day), folic acid (0.8 mg/day), DHA (800 mg/day), and placebo, for 6 months. Cognitive function and blood amyloid-β peptide (Aβ) biomarker levels were measured at baseline and 6 months. Cognitive function was also measured at 12 months. Results: A total of 138 patients completed this trial. Folic acid improved the full-scale intelligence quotient (FSIQ), arithmetic, and picture complement scores; DHA improved the FSIQ, information, arithmetic, and digit span scores; folic acid + DHA improved the arithmetic (difference 1.67, 95% CI 1.02 to 2.31) and digital span (1.33, 0.24 to 2.43) scores compared to placebo. At 12 months, all scores declined in the intervention groups. Folic acid and folic acid + DHA increased blood folate (folic acid + DHA: 7.70, 3.81 to 11.59) and S-adenosylmethionine (23.93, 1.86 to 46.00) levels and reduced homocysteine levels (–6.51, –10.57 to –2.45) compared to placebo. DHA lower the Aβ40 levels (–40.57, –79.79 to –1.35) compared to placebo (p < 0.05), and folic acid + DHA reduced the Aβ42 (–95.59, –150.76 to –40.43) and Aβ40 levels (–45.75, –84.67 to –6.84) more than DHA (p < 0.05). Conclusion: Folic acid and DHA improve cognitive function and reduce blood Aβ production in MCI patients. Combination therapy may be more beneficial in reducing blood Aβ-related biomarkers.

Download Full-text

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

Antioxidants ◽

10.3390/antiox8120630 ◽

2019 ◽

Vol 8 (12) ◽

pp. 630 ◽

Cited By ~ 6

Author(s):

Donald G Matthews ◽

Maya Caruso ◽

Charles F Murchison ◽

Jennifer Y Zhu ◽

Kirsten M Wright ◽

...

Keyword(s):

Oxidative Stress ◽

Amyloid Β ◽

Water Extract ◽

Centella Asiatica ◽

Antioxidant Response ◽

Plaque Burden ◽

Heme Oxygenase 1 ◽

Synaptic Density ◽

Cognitive Benefits ◽

5Xfad Mice

Centella asiatica (CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer’s disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ − 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW’s impact on amyloid-β plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.

Download Full-text

Physical Activity and Amyloid-β Brain Levels in Elderly Adults with Intact Cognition and Mild Cognitive Impairment

Journal of the American Geriatrics Society ◽

10.1111/jgs.13530 ◽

2015 ◽

Vol 63 (8) ◽

pp. 1634-1639 ◽

Cited By ~ 23

Author(s):

Philipe de Souto Barreto ◽

Sandrine Andrieu ◽

Pierre Payoux ◽

Laurent Demougeot ◽

Yves Rolland ◽

...

Keyword(s):

Physical Activity ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Amyloid Β ◽

Elderly Adults ◽

Brain Levels

Download Full-text

Lipidomic Network of Mild Cognitive Impairment from the Mayo Clinic Study of Aging

Journal of Alzheimer s Disease ◽

10.3233/jad-201347 ◽

2021 ◽

pp. 1-11

Author(s):

Xuewei Wang ◽

Hai Bui ◽

Prashanthi Vemuri ◽

Jonathan Graff-Radford ◽

Clifford R. Jack Jr ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Network Analysis ◽

Mayo Clinic ◽

Plasma Lipids ◽

Amyloid Β ◽

Cognitive Status ◽

Correlation Network ◽

Lipid Species ◽

Clinic Study

Background: Lipid alterations contribute to Alzheimer’s disease (AD) pathogenesis. Lipidomics studies could help systematically characterize such alterations and identify potential biomarkers. Objective: To identify lipids associated with mild cognitive impairment and amyloid-β deposition, and to examine lipid correlation patterns within phenotype groups Methods: Eighty plasma lipids were measured using mass spectrometry for 1,255 non-demented participants enrolled in the Mayo Clinic Study of Aging. Individual lipids associated with mild cognitive impairment (MCI) were first identified. Correlation network analysis was then performed to identify lipid species with stable correlations across conditions. Finally, differential correlation network analysis was used to determine lipids with altered correlations between phenotype groups, specifically cognitively unimpaired versus MCI, and with elevated brain amyloid versus without. Results: Seven lipids were associated with MCI after adjustment for age, sex, and APOE4. Lipid correlation network analysis revealed that lipids from a few species correlated well with each other, demonstrated by subnetworks of these lipids. 177 lipid pairs differently correlated between cognitively unimpaired and MCI patients, whereas 337 pairs of lipids exhibited altered correlation between patients with and without elevated brain amyloid. In particular, 51 lipid pairs showed correlation alterations by both cognitive status and brain amyloid. Interestingly, the lipids central to the network of these 51 lipid pairs were not significantly associated with either MCI or amyloid, suggesting network-based approaches could provide biological insights complementary to traditional association analyses. Conclusion: Our attempt to characterize the alterations of lipids at network-level provides additional insights beyond individual lipids, as shown by differential correlations in our study.

Download Full-text

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.

Download Full-text