Amyloid Beta-Related Alterations to Glutamate Signaling Dynamics During Alzheimer’s Disease Progression

Alzheimer’s disease (AD) ranks sixth on the Centers for Disease Control and Prevention Top 10 Leading Causes of Death list for 2016, and the Alzheimer’s Association attributes 60% to 80% of dementia cases as AD related. AD pathology hallmarks include accumulation of senile plaques and neurofibrillary tangles; however, evidence supports that soluble amyloid beta (Aβ), rather than insoluble plaques, may instigate synaptic failure. Soluble Aβ accumulation results in depression of long-term potentiation leading to cognitive deficits commonly characterized in AD. The mechanisms through which Aβ incites cognitive decline have been extensively explored, with a growing body of evidence pointing to modulation of the glutamatergic system. The period of glutamatergic hypoactivation observed alongside long-term potentiation depression and cognitive deficits in later disease stages may be the consequence of a preceding period of increased glutamatergic activity. This review will explore the Aβ-related changes to the tripartite glutamate synapse resulting in altered cell signaling throughout disease progression, ultimately culminating in oxidative stress, synaptic dysfunction, and neuronal loss.

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Differential Inhibition of E-S Potentiation and Long-term Potentiation by Cell-derived and Arctic Amyloid Beta

10.1101/601492 ◽

2019 ◽

Author(s):

Adrienne L. Orr ◽

Jason K. Clark ◽

Daniel V. Madison

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Hippocampal Slices ◽

Memory Deficits ◽

Long Term Potentiation ◽

Amyloid Beta Peptide ◽

Term Potentiation ◽

Beta Peptide

AbstractSoluble oligomers of amyloid-beta peptide (Abeta) have been implicated in the onset of memory deficits in Alzheimer’s disease, perhaps due to their reported ability to impair long-term potentiation (LTP) of synaptic strength. We previously showed the effect of Abeta on LTP depends on the strength of LTP induction. Furthermore, Abeta affects EPSP-Spike (E-S) potentiation more robustly than LTP, suggesting that E-S potentiation may be equally important to learning and memory in the context of Alzheimer’s disease. Here we extend our findings to two additional forms of Abeta that form higher concentrations of soluble Abeta oligomers and show that they also affect E-S potentiation at induction strengths where there is no effect on LTP in hippocampal slices.

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Neuroprotective properties of mitochondria-targeted antioxidants of the SkQ-type

Reviews in the Neurosciences ◽

10.1515/revneuro-2016-0036 ◽

2016 ◽

Vol 27 (8) ◽

pp. 849-855 ◽

Cited By ~ 17

Author(s):

Nickolay K. Isaev ◽

Elena V. Stelmashook ◽

Elisaveta E. Genrikhs ◽

Galina A. Korshunova ◽

Natalya V. Sumbatyan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Area ◽

Hippocampal Slices ◽

Amyloid Β ◽

Long Term Potentiation ◽

Term Potentiation ◽

Neuroprotective Action

AbstractIn 2008, using a model of compression brain ischemia, we presented the first evidence that mitochondria-targeted antioxidants of the SkQ family, i.e. SkQR1 [10-(6′-plastoquinonyl)decylrhodamine], have a neuroprotective action. It was shown that intraperitoneal injections of SkQR1 (0.5–1 μmol/kg) 1 day before ischemia significantly decreased the damaged brain area. Later, we studied in more detail the anti-ischemic action of this antioxidant in a model of experimental focal ischemia provoked by unilateral intravascular occlusion of the middle cerebral artery. The neuroprotective action of SkQ family compounds (SkQR1, SkQ1, SkQTR1, SkQT1) was manifested through the decrease in trauma-induced neurological deficit in animals and prevention of amyloid-β-induced impairment of long-term potentiation in rat hippocampal slices. At present, most neurophysiologists suppose that long-term potentiation underlies cellular mechanisms of memory and learning. They consider inhibition of this process by amyloid-β1-42as anin vitromodel of memory disturbance in Alzheimer’s disease. Further development of the above studies revealed that mitochondria-targeted antioxidants could retard accumulation of hyperphosphorylated τ-protein, as well as amyloid-β1-42, and its precursor APP in the brain, which are involved in developing neurodegenerative processes in Alzheimer’s disease.

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Progressive Age-Related Impairment of the Late Long-Term Potentiation in Alzheimer's Disease Presenilin-1 Mutant Knock-in Mice

Journal of Alzheimer s Disease ◽

10.3233/jad-2010-1302 ◽

2010 ◽

Vol 19 (3) ◽

pp. 1021-1033 ◽

Cited By ~ 29

Author(s):

Alexandra Auffret ◽

Vanessa Gautheron ◽

Mark P. Mattson ◽

Jean Mariani ◽

Catherine Rovira

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Long Term Potentiation ◽

Presenilin 1 ◽

Age Related ◽

Term Potentiation

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TDP-43 interacts with amyloid-β, inhibits fibrillization, and worsens pathology in a model of Alzheimer’s disease

Nature Communications ◽

10.1038/s41467-020-19786-7 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Yao-Hsiang Shih ◽

Ling-Hsien Tu ◽

Ting-Yu Chang ◽

Kiruthika Ganesan ◽

Wei-Wei Chang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Long Term Potentiation ◽

Model Of Alzheimer’S Disease ◽

Term Potentiation ◽

Spatial Memory Deficit ◽

Aβ Aggregation ◽

Intrahippocampal Injection

AbstractTDP-43 inclusions are found in many Alzheimer’s disease (AD) patients presenting faster disease progression and greater brain atrophy. Previously, we showed full-length TDP-43 forms spherical oligomers and perturbs amyloid-β (Aβ) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Aβ aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited Aβ fibrillization at initial and oligomeric stages. Aβ fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Aβ interaction. TDP-43 significantly enhanced Aβ’s ability to impair long-term potentiation and, upon intrahippocampal injection, caused spatial memory deficit. Following injection to AD transgenic mice, TDP-43 induced inflammation, interacted with Aβ, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular Aβ in the brain of AD patients. We conclude that TDP-43 inhibits Aβ fibrillization through its interaction with Aβ and exacerbates AD pathology.

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Emerging Link between Alzheimer’s Disease and Homeostatic Synaptic Plasticity

Neural Plasticity ◽

10.1155/2016/7969272 ◽

2016 ◽

Vol 2016 ◽

pp. 1-19 ◽

Cited By ~ 29

Author(s):

Sung-Soo Jang ◽

Hee Jung Chung

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Senile Plaques ◽

Long Term Potentiation ◽

Brain Regions ◽

Synaptic Activity ◽

Homeostatic Plasticity ◽

Brain Disorder

Alzheimer’s disease (AD) is an irreversible brain disorder characterized by progressive cognitive decline and neurodegeneration of brain regions that are crucial for learning and memory. Although intracellular neurofibrillary tangles and extracellular senile plaques, composed of insoluble amyloid-β(Aβ) peptides, have been the hallmarks of postmortem AD brains, memory impairment in early AD correlates better with pathological accumulation of soluble Aβoligomers and persistent weakening of excitatory synaptic strength, which is demonstrated by inhibition of long-term potentiation, enhancement of long-term depression, and loss of synapses. However, current, approved interventions aiming to reduce Aβlevels have failed to retard disease progression; this has led to a pressing need to identify and target alternative pathogenic mechanisms of AD. Recently, it has been suggested that the disruption of Hebbian synaptic plasticity in AD is due to aberrant metaplasticity, which is a form of homeostatic plasticity that tunes the magnitude and direction of future synaptic plasticity based on previous neuronal or synaptic activity. This review examines emerging evidence for aberrant metaplasticity in AD. Putative mechanisms underlying aberrant metaplasticity in AD will also be discussed. We hope this review inspires future studies to test the extent to which these mechanisms contribute to the etiology of AD and offer therapeutic targets.

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Decision letter for "Maintained memory and long‐term potentiation in a mouse model of Alzheimer’s disease with both amyloid pathology and human tau"

10.1111/ejn.14918/v2/decision1 ◽

2020 ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Long Term Potentiation ◽

Amyloid Pathology ◽

Model Of Alzheimer’S Disease ◽

Term Potentiation

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Cyclase-associated protein 2 dimerization regulates cofilin in synaptic plasticity and Alzheimer's disease

Brain Communications ◽

10.1093/braincomms/fcaa086 ◽

2020 ◽

Vol 2 (2) ◽

Cited By ~ 3

Author(s):

Silvia Pelucchi ◽

Lina Vandermeulen ◽

Lara Pizzamiglio ◽

Bahar Aksan ◽

Jing Yan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Actin Cytoskeleton ◽

Structural Plasticity ◽

Long Term Potentiation ◽

Brain Diseases ◽

Biological Trait ◽

Term Potentiation ◽

Cytoskeleton Dynamics

Abstract Regulation of actin cytoskeleton dynamics in dendritic spines is crucial for learning and memory formation. Hence, defects in the actin cytoskeleton pathways are a biological trait of several brain diseases, including Alzheimer's disease. Here, we describe a novel synaptic mechanism governed by the cyclase-associated protein 2, which is required for structural plasticity phenomena and completely disrupted in Alzheimer's disease. We report that the formation of cyclase-associated protein 2 dimers through its Cys32 is important for cyclase-associated protein 2 binding to cofilin and for actin turnover. The Cys32-dependent cyclase-associated protein 2 homodimerization and association to cofilin are triggered by long-term potentiation and are required for long-term potentiation-induced cofilin translocation into spines, spine remodelling and the potentiation of synaptic transmission. This mechanism is specifically affected in the hippocampus, but not in the superior frontal gyrus, of both Alzheimer's disease patients and APP/PS1 mice, where cyclase-associated protein 2 is down-regulated and cyclase-associated protein 2 dimer synaptic levels are reduced. Notably, cyclase-associated protein 2 levels in the cerebrospinal fluid are significantly increased in Alzheimer's disease patients but not in subjects affected by frontotemporal dementia. In Alzheimer's disease hippocampi, cofilin association to cyclase-associated protein 2 dimer/monomer is altered and cofilin is aberrantly localized in spines. Taken together, these results provide novel insights into structural plasticity mechanisms that are defective in Alzheimer's disease.

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