scholarly journals Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Swagata Ghatak ◽  
Nima Dolatabadi ◽  
Dorit Trudler ◽  
XiaoTong Zhang ◽  
Yin Wu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sodium Current ◽  
Underlying Mechanism ◽  
Synaptic Activity ◽  
Neuronal Cultures ◽  
Neurite Length ◽  
Mechanistic Insight ◽  
Immunofluorescence Studies ◽  
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Human Alzheimer’s disease (AD) brains and transgenic AD mouse models manifest hyperexcitability. This aberrant electrical activity is caused by synaptic dysfunction that represents the major pathophysiological correlate of cognitive decline. However, the underlying mechanism for this excessive excitability remains incompletely understood. To investigate the basis for the hyperactivity, we performed electrophysiological and immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures and cerebral organoids bearing AD-related mutations in presenilin-1 or amyloid precursor protein vs. isogenic gene corrected controls. In the AD hiPSC-derived neurons/organoids, we found increased excitatory bursting activity, which could be explained in part by a decrease in neurite length. AD hiPSC-derived neurons also displayed increased sodium current density and increased excitatory and decreased inhibitory synaptic activity. Our findings establish hiPSC-derived AD neuronal cultures and organoids as a relevant model of early AD pathophysiology and provide mechanistic insight into the observed hyperexcitability.

Mechanistic insight into the role of metformin in Alzheimer's disease

Life Sciences ◽  
2022 ◽  
pp. 120299
Author(s):  
Mehdi Sanati ◽  
Samaneh Aminyavari ◽  
Amir R. Afshari ◽  
Amirhossein Sahebkar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mechanistic Insight ◽  
Insight Into

scholarly journals Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer’s disease neurons

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Prasad Tammineni ◽  
Xuan Ye ◽  
Tuancheng Feng ◽  
Daniyal Aikal ◽  
Qian Cai
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Retrograde Transport ◽  
Presynaptic Terminals ◽  
Aβ Oligomers ◽  
Autophagic Vacuoles ◽  
Axonal Pathology ◽  
Mechanistic Insight ◽  
Insight Into

Neurons face unique challenges of transporting nascent autophagic vacuoles (AVs) from distal axons toward the soma, where mature lysosomes are mainly located. Autophagy defects have been linked to Alzheimer’s disease (AD). However, the mechanisms underlying altered autophagy remain unknown. Here, we demonstrate that defective retrograde transport contributes to autophagic stress in AD axons. Amphisomes predominantly accumulate at axonal terminals of mutant hAPP mice and AD patient brains. Amyloid-β (Aβ) oligomers associate with AVs in AD axons and interact with dynein motors. This interaction impairs dynein recruitment to amphisomes through competitive interruption of dynein-Snapin motor-adaptor coupling, thus immobilizing them in distal axons. Consistently, deletion of Snapin in mice causes AD-like axonal autophagic stress, whereas overexpressing Snapin in hAPP neurons reduces autophagic accumulation at presynaptic terminals by enhancing AV retrograde transport. Altogether, our study provides new mechanistic insight into AD-associated autophagic stress, thus establishing a foundation for ameliorating axonal pathology in AD.

Voxel-based morphometry (VBM) analysis in Alzheimer's disease an insight into heterogeneity of cerebral atrophy

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S338-S338
Author(s):  
Akihiko Shiino ◽  
Toshiyuki Watanabe ◽  
Ichiro Akiguchi ◽  
Shigehiro Morikawa ◽  
Toshiro Inubushi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Atrophy ◽  
Voxel Based Morphometry ◽  
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scholarly journals Interactions between sleep disturbances and Alzheimer’s disease on brain function: a preliminary study combining the static and dynamic functional MRI

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kaicheng Li ◽  
Xiao Luo ◽  
Qingze Zeng ◽  
Yerfan Jiaerken ◽  
Shuyue Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Sleep Disturbance ◽  
Brain Function ◽  
Sleep Disturbances ◽  
Brain Activity ◽  
Vascular Risk Factor ◽  
Underlying Mechanism ◽  
Amyloid Pet

AbstractThough sleep disturbance constitutes the risk factor for Alzheimer’s disease (AD), the underlying mechanism is still unclear. This study aims to explore the interaction between sleep disturbances and AD on brain function. We included 192 normal controls, 111 mild cognitive impairment (MCI), and 30 AD patients, with either poor or normal sleep (PS, NS, respectively). To explore the strength and stability of brain activity, we used static amplitude of low-frequency fluctuation (sALFF) and dynamic ALFF (dALFF) variance. Further, we examined white matter hyperintensities (WMH) and amyloid PET deposition, representing the vascular risk factor and AD-related hallmark, respectively. We observed that sleep disturbance significantly interacted with disease severity, exposing distinct effects on sALFF and dALFF variance. Interestingly, PS groups showed the dALFF variance trajectory of initially increased, then decreased and finally increased along the AD spectrum, while showing the opposite trajectory of sALFF. Further correlation analysis showed that the WMH burden correlates with dALFF variance in PS groups. Conclusively, our study suggested that sleep disturbance interacts with AD severity, expressing as effects of compensatory in MCI and de-compensatory in AD, respectively. Further, vascular impairment might act as important pathogenesis underlying the interaction effect between sleep and AD.

scholarly journals Continuous and Cyclic Progesterone Differentially Interact with Estradiol in the Regulation of Alzheimer-Like Pathology in Female 3×Transgenic-Alzheimer’s Disease Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2713-2722 ◽  
Author(s):  
Jenna C. Carroll ◽  
Emily R. Rosario ◽  
Angela Villamagna ◽  
Christian J. Pike
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Postmenopausal Women ◽  
Transgenic Mouse Model ◽  
Dependent Behavior ◽  
Potential Efficacy ◽  
Increased Risk ◽  
Neural Interactions ◽  
Β Amyloid ◽  
Insight Into

Depletion of estrogens and progesterone at menopause has been linked to an increased risk for the development of Alzheimer’s disease (AD) in women. A currently controversial literature indicates that although treatment of postmenopausal women with hormone therapy (HT) may reduce the risk of AD, several parameters of HT may limit its potential efficacy and perhaps, even exacerbate AD risk. One such parameter is continuous vs. cyclic delivery of the progestogen component of HT. Recent experimental evidence suggests that continuous progesterone can attenuate neural actions of estradiol (E2). In the present study, we compared the effects of continuous and cyclic progesterone treatment in the presence and absence of E2 in ovariectomized 3×Tg-AD mice, a transgenic mouse model of AD. We found that ovariectomy-induced hormone depletion increases AD-like pathology in female 3×Tg-AD mice, including accumulation of β-amyloid, tau hyperphosphorylation, and impaired hippocampal-dependent behavior. E2 treatment alone prevents the increases in pathology. Continuous progesterone did not affect β-amyloid levels when delivered alone but blocked the Aβ-lowering action of E2. In contrast, cyclic progesterone significantly reduced β-amyloid levels by itself and enhanced rather than inhibited the E2 effects. These results provide new insight into the neural interactions between E2 and progesterone that may prove valuable in optimizing HT regimens in postmenopausal women.

scholarly journals Specks of insight into Alzheimer’s disease

Nature ◽  
2017 ◽  
Vol 552 (7685) ◽  
pp. 342-343 ◽  
Author(s):  
Richard M. Ransohoff
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Insight Into
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