O3-01-01: Amyloid-β protofibrils are linked to cognitive impairment in Alzheimer's disease transgenic mice

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.

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Sulforaphane Inhibits the Generation of Amyloid-β Oligomer and Promotes Spatial Learning and Memory in Alzheimer’s Disease (PS1V97L) Transgenic Mice

Journal of Alzheimer s Disease ◽

10.3233/jad-171110 ◽

2018 ◽

Vol 62 (4) ◽

pp. 1803-1813 ◽

Cited By ~ 19

Author(s):

Ting-Ting Hou ◽

He-Yun Yang ◽

Wei Wang ◽

Qiao-Qi Wu ◽

Yuan-Ruhua Tian ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Learning And Memory ◽

Spatial Learning ◽

Amyloid Β ◽

Spatial Learning And Memory

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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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Gut Microbiota Alterations and Cognitive Impairment Are Sexually Dissociated in a Transgenic Mice Model of Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201367 ◽

2021 ◽

pp. 1-20

Author(s):

Daniel Cuervo-Zanatta ◽

Jaime Garcia-Mena ◽

Claudia Perez-Cruz

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Gut Microbiota ◽

Cognitive Skills ◽

Amyloid Β ◽

Short Chain Fatty Acids ◽

Mice Model ◽

Model Of Alzheimer’S Disease ◽

Cognitive Deficiencies

Background: Normal aging is accompanied by cognitive deficiencies, affecting women and men equally. Aging is the main risk factor for Alzheimer’s disease (AD), with women having a higher risk. The higher prevalence of AD in women is associated with the abrupt hormonal decline seen after menopause. However, other factors may be involved in this sex-related cognitive decline. Alterations in gut microbiota (GM) and its bioproducts have been reported in AD subjects and transgenic (Tg) mice, having a direct impact on brain amyloid-β pathology in male (M), but not in female (F) mice. Objective: The aim of this work was to determine GM composition and cognitive dysfunction in M and F wildtype (WT) and Tg mice, in a sex/genotype segregation design. Methods: Anxiety, short term working-memory, spatial learning, and long-term spatial memory were evaluated in 6-month-old WT and Tg male mice. Fecal short chain fatty acids were determined by chromatography, and DNA sequencing and bioinformatic analyses were used to determine GM differences. Results: We observed sex-dependent differences in cognitive skills in WT mice, favoring F mice. However, the cognitive advantage of females was lost in Tg mice. GM composition showed few sex-related differences in WT mice. Contrary, Tg-M mice presented a more severe dysbiosis than Tg-F mice. A decreased abundance of Ruminococcaceae was associated with cognitive deficits in Tg-F mice, while butyrate levels were positively associated with better working- and object recognition-memory in WT-F mice. Conclusion: This report describes a sex-dependent association between GM alterations and cognitive impairment in a mice model of AD.

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Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer’s disease and mild cognitive impairment

Brain ◽

10.1093/brain/awu043 ◽

2014 ◽

Vol 137 (5) ◽

pp. 1550-1561 ◽

Cited By ~ 79

Author(s):

Niklas Mattsson ◽

Duygu Tosun ◽

Philip S. Insel ◽

Alix Simonson ◽

Clifford R Jack ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cerebral Perfusion ◽

Amyloid Β

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Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-β Levels in Aged Alzheimer's Disease Mice

Journal of Alzheimer s Disease ◽

10.3233/jad-2009-1087 ◽

2009 ◽

Vol 17 (3) ◽

pp. 661-680 ◽

Cited By ~ 143

Author(s):

Gary W. Arendash ◽

Takashi Mori ◽

Chuanhai Cao ◽

Malgorzata Mamcarz ◽

Melissa Runfeldt ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Amyloid Β

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The Role of Apolipoprotein E ε4 in Early and Late Mild Cognitive Impairment

European Neurology ◽

10.1159/000516774 ◽

2021 ◽

Vol 84 (6) ◽

pp. 472-480

Author(s):

Yulin Luo ◽

Li Tan ◽

Joseph Therriault ◽

Hua Zhang ◽

Ying Gao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Apolipoprotein E ◽

Amyloid Β ◽

Disease Assessment ◽

Tau Pathology ◽

Ε4 Allele ◽

State Examination

Background: Apolipoprotein E (APOE) ε4 is highly associated with mild cognitive impairment (MCI). However, the specific influence of APOE ε4 status on tau pathology and cognitive decline in early MCI (EMCI) and late MCI (LMCI) is poorly understood. Our goal was to evaluate the association of APOE ε4 with cerebrospinal fluid (CSF) tau levels and cognition in EMCI and LMCI patients in the Alzheimer’s Disease Neuroimaging Initiative database, and whether this association was mediated by amyloid-β (Aβ). Methods: Participants were 269 cognitively normal (CN), 262 EMCI, and 344 LMCI patients. They underwent CSF Aβ42 and tau detection, APOE ε4 genotyping, Mini-Mental State Examination, (MMSE), and Alzheimer’s disease assessment scale (ADAS)-cog assessments. Linear regressions were used to examine the relation of APOE ε4 and CSF tau levels and cognitive scores in persons with and without Aβ deposition (Aβ+ and Aβ−). Results: The prevalence of APOE ε4 is higher in EMCI and LMCI than in CN (p < 0.001 for both), and in LMCI than in EMCI (p = 0.001). APOE ε4 allele was significantly higher in Aβ+ subjects than in Aβ− subjects (p < 0.001). Subjects who had a lower CSF Aβ42 level and were APOE ε4-positive experienced higher levels of CSF tau and cognitive scores in EMCI and/or LMCI. Conclusions: An APOE ε4 allele is associated with increased CSF tau and worse cognition in both EMCI and LMCI, and this association may be mediated by Aβ. We conclude that APOE ε4 may be an important mediator of tau pathology and cognition in the early stages of AD.

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Reduced non–rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease

Science Translational Medicine ◽

10.1126/scitranslmed.aau6550 ◽

2019 ◽

Vol 11 (474) ◽

pp. eaau6550 ◽

Cited By ~ 65

Author(s):

Brendan P. Lucey ◽

Austin McCullough ◽

Eric C. Landsness ◽

Cristina D. Toedebusch ◽

Jennifer S. McLeland ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Eye Movement ◽

Single Channel ◽

Amyloid Β ◽

Neuronal Cell ◽

Rapid Eye Movement ◽

Tau Pathology ◽

Potential Marker

In Alzheimer’s disease (AD), deposition of insoluble amyloid-β (Aβ) is followed by intracellular aggregation of tau in the neocortex and subsequent neuronal cell loss, synaptic loss, brain atrophy, and cognitive impairment. By the time even the earliest clinical symptoms are detectable, Aβ accumulation is close to reaching its peak and neocortical tau pathology is frequently already present. The period in which AD pathology is accumulating in the absence of cognitive symptoms represents a clinically relevant time window for therapeutic intervention. Sleep is increasingly recognized as a potential marker for AD pathology and future risk of cognitive impairment. Previous studies in animal models and humans have associated decreased non–rapid eye movement (NREM) sleep slow wave activity (SWA) with Aβ deposition. In this study, we analyzed cognitive performance, brain imaging, and cerebrospinal fluid (CSF) AD biomarkers in participants enrolled in longitudinal studies of aging. In addition, we monitored their sleep using a single-channel electroencephalography (EEG) device worn on the forehead. After adjusting for multiple covariates such as age and sex, we found that NREM SWA showed an inverse relationship with AD pathology, particularly tauopathy, and that this association was most evident at the lowest frequencies of NREM SWA. Given that our study participants were predominantly cognitively normal, this suggested that changes in NREM SWA, especially at 1 to 2 Hz, might be able to discriminate tau pathology and cognitive impairment either before or at the earliest stages of symptomatic AD.

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N,N′-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer’s disease transgenic mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1916318116 ◽

2019 ◽

Vol 116 (47) ◽

pp. 23426-23436 ◽

Cited By ~ 6

Author(s):

Min Hee Park ◽

Misun Lee ◽

Geewoo Nam ◽

Mingeun Kim ◽

Juhye Kang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Amyloid Β ◽

Causative Factor ◽

Central Feature ◽

Microglial Phagocytosis ◽

Cognitive Defects

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N′-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-β (Aβ) species and significantly improving cognitive function in the brains of 2 types of Alzheimer’s disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aβ clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

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