Mechanistic Insight into the Design of Chemical Tools to Control Multiple Pathogenic Features in Alzheimer’s Disease

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.

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

eLife ◽

10.7554/elife.50333 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 18

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 ◽

Insight Into

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.

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Mechanistic insight into the capacity of natural polar phenolic compounds to abolish Alzheimer’s disease-associated pathogenic effects of apoE4 forms

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2021.05.022 ◽

2021 ◽

Author(s):

Christina Mountaki ◽

Ioannis Dafnis ◽

Eirini A. Panagopoulou ◽

Paraskevi B. Vasilakopoulou ◽

Michalis Karvelas ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Phenolic Compounds ◽

Mechanistic Insight ◽

Insight Into ◽

Pathogenic Effects

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9591524.0338 ◽

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 ◽

Insight Into

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Insight into the Epigenetics of Alzheimer's Disease: A Computational Study from Human Interactome

Current Alzheimer Research ◽

10.2174/1567205013666160803151101 ◽

2016 ◽

Vol 13 (12) ◽

pp. 1385-1396 ◽

Cited By ~ 4

Author(s):

Paulami Chatterjee ◽

Debjani Roy

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Computational Study ◽

Human Interactome ◽

Insight Into

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

Endocrinology ◽

10.1210/en.2009-1487 ◽

2010 ◽

Vol 151 (6) ◽

pp. 2713-2722 ◽

Cited By ~ 57

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.

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