Synaptic plasticity in Alzheimer’s disease and healthy aging

AbstractThe strength and efficiency of synaptic connections are affected by the environment or the experience of the individual. This property, called synaptic plasticity, is directly related to memory and learning processes and has been modeled at the cellular level. These types of cellular memory and learning models include specific stimulation protocols that generate a long-term strengthening of the synapses, called long-term potentiation, or a weakening of the said long-term synapses, called long-term depression. Although, for decades, researchers have believed that the main cause of the cognitive deficit that characterizes Alzheimer’s disease (AD) and aging was the loss of neurons, the hypothesis of an imbalance in the cellular and molecular mechanisms of synaptic plasticity underlying this deficit is currently widely accepted. An understanding of the molecular and cellular changes underlying the process of synaptic plasticity during the development of AD and aging will direct future studies to specific targets, resulting in the development of much more efficient and specific therapeutic strategies. In this review, we classify, discuss, and describe the main findings related to changes in the neurophysiological mechanisms of synaptic plasticity in excitatory synapses underlying AD and aging. In addition, we suggest possible mechanisms in which aging can become a high-risk factor for the development of AD and how its development could be prevented or slowed.

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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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Potentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer's disease

Journal of Neuroinflammation ◽

10.1186/s12974-021-02276-y ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Gonzalo Ruiz-Pérez ◽

Samuel Ruiz de Martín Esteban ◽

Sharai Marqués ◽

Noelia Aparicio ◽

M. Teresa Grande ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Synaptic Transmission ◽

Amyloid Beta ◽

Molecular Mechanisms ◽

Long Term Potentiation ◽

Genetic Inactivation ◽

5Xfad Mouse

Abstract Background The complex pathophysiology of Alzheimer’s disease (AD) hampers the development of effective treatments. Attempts to prevent neurodegeneration in AD have failed so far, highlighting the need for further clarification of the underlying cellular and molecular mechanisms. Neuroinflammation seems to play a crucial role in disease progression, although its specific contribution to AD pathogenesis remains elusive. We have previously shown that the modulation of the endocannabinoid system (ECS) renders beneficial effects in a context of amyloidosis, which triggers neuroinflammation. In the 5xFAD model, the genetic inactivation of the enzyme that degrades anandamide (AEA), the fatty acid amide hydrolase (FAAH), was associated with a significant amelioration of the memory deficit. Methods In this work, we use electrophysiology, flow cytometry and molecular analysis to evaluate the cellular and molecular mechanisms underlying the improvement associated to the increased endocannabinoid tone in the 5xFAD mouse− model. Results We demonstrate that the chronic enhancement of the endocannabinoid tone rescues hippocampal synaptic plasticity in the 5xFAD mouse model. At the CA3–CA1 synapse, both basal synaptic transmission and long-term potentiation (LTP) of synaptic transmission are normalized upon FAAH genetic inactivation, in a CB1 receptor (CB1R)- and TRPV1 receptor-independent manner. Dendritic spine density in CA1 pyramidal neurons, which is notably decreased in 6-month-old 5xFAD animals, is also restored. Importantly, we reveal that the expression of microglial factors linked to phagocytic activity, such as TREM2 and CTSD, and other factors related to amyloid beta clearance and involved in neuron–glia crosstalk, such as complement component C3 and complement receptor C3AR, are specifically upregulated in 5xFAD/FAAH−/− animals. Conclusion In summary, our findings support the therapeutic potential of modulating, rather than suppressing, neuroinflammation in Alzheimer’s disease. In our model, the long-term enhancement of the endocannabinoid tone triggered augmented microglial activation and amyloid beta phagocytosis, and a consequent reversal in the neuronal phenotype associated to the disease.

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Estrogen and hippocampal synaptic plasticity

Neuron Glia Biology ◽

10.1017/s1740925x05000165 ◽

2004 ◽

Vol 1 (4) ◽

pp. 327-338 ◽

Cited By ~ 9

Author(s):

MICHAEL FOY ◽

MICHEL BAUDRY ◽

RICHARD THOMPSON

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Clinical Studies ◽

Molecular Mechanisms ◽

Estrogen Therapy ◽

Long Term Potentiation ◽

Neural Function ◽

Term Potentiation ◽

Primary Focus

During the past several years, there has been increasing interest in the effects of estrogen on neural function. This enthusiasm is driven, in part, by the results of early clinical studies suggesting that estrogen therapy given after menopause may prevent, or at least delay, the onset of Alzheimer's disease in older women. However, later clinical trials of women with probable Alzheimer's disease had contrary results. Much of the current research related to estrogen and brain function is focused in two directions. One involves clinical studies that examine the potential of estrogen in protecting against cognitive decline during normal aging and against Alzheimer's disease (neuroprotection). The other direction, which is the primary focus of this review, involves laboratory studies that examine the mechanisms by which estrogen can modify the structure of nerve cells and alter the way neurons communicate with other cells in the brain (neuroplasticity). In this review, we examine recent evidence from experimental and clinical research on the rapid effects of estrogen on several mechanisms that involve synaptic plasticity in the nervous system, including hippocampal excitability, long-term potentiation and depression related to sex and aging differences, cellular neuroprotection and probable molecular mechanisms of the action of estrogen in brain tissue.

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Enduring glucocorticoid-evoked exacerbation of synaptic plasticity disruption in male rats modelling early Alzheimer’s disease amyloidosis

Neuropsychopharmacology ◽

10.1038/s41386-021-01056-9 ◽

2021 ◽

Author(s):

Yingjie Qi ◽

Igor Klyubin ◽

Tomas Ondrejcak ◽

Neng-Wei Hu ◽

Michael J. Rowan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Transgenic Animals ◽

Long Term Potentiation ◽

Male Rats ◽

Model Of Alzheimer’S Disease ◽

Term Potentiation ◽

Early Alzheimer’S Disease

AbstractSynaptic dysfunction is a likely proximate cause of subtle cognitive impairment in early Alzheimer’s disease. Soluble oligomers are the most synaptotoxic forms of amyloid ß-protein (Aß) and mediate synaptic plasticity disruption in Alzheimer’s disease amyloidosis. Because the presence and extent of cortisol excess in prodromal Alzheimer’s disease predicts the onset of cognitive symptoms we hypothesised that corticosteroids would exacerbate the inhibition of hippocampal synaptic long-term potentiation in a rat model of Alzheimer’s disease amyloidosis. In a longitudinal experimental design using freely behaving pre-plaque McGill-R-Thy1-APP male rats, three injections of corticosterone or the glucocorticoid methylprednisolone profoundly disrupted long-term potentiation induced by strong conditioning stimulation for at least 2 months. The same treatments had a transient or no detectible detrimental effect on synaptic plasticity in wild-type littermates. Moreover, corticosterone-mediated cognitive dysfunction, as assessed in a novel object recognition test, was more persistent in the transgenic animals. Evidence for the involvement of pro-inflammatory mechanisms was provided by the ability of the selective the NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome inhibitor Mcc950 to reverse the synaptic plasticity deficit in corticosterone-treated transgenic animals. The marked prolongation of the synaptic plasticity disrupting effects of brief corticosteroid excess substantiates a causal role for hypothalamic-pituitary-adrenal axis dysregulation in early Alzheimer’s disease.

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CAP2 is a novel regulator of Cofilin in synaptic plasticity and Alzheimer’s disease

10.1101/789552 ◽

2019 ◽

Author(s):

Silvia Pelucchi ◽

Lina Vandermeulen ◽

Lara Pizzamiglio ◽

Bahar Aksan ◽

Jing Yan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Synaptic Transmission ◽

Long Term Potentiation ◽

Actin Dynamics ◽

Term Potentiation ◽

Actin Turnover ◽

Normal Spine

AbstractCofilin is one of the major regulators of actin dynamics in spines where it is required for structural synaptic plasticity. However, our knowledge of the mechanisms controlling Cofilin activity in spines remains still fragmented. Here, we describe the cyclase-associated protein 2 (CAP2) as a novel master regulator of Cofilin localization in spines. The formation of CAP2 dimers through its Cys32 is important for CAP2 binding to Cofilin and for normal spine actin turnover. The Cys32-dependent CAP2 homodimerization and association to Cofilin are triggered by long-term potentiation (LTP) and are required for LTP-induced Cofilin translocation into spines, spine remodeling 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 (AD) patients and APP/PS1 mice, where CAP2 is down-regulated and CAP2 dimer synaptic levels are reduced. In AD hippocampi, Cofilin preferentially associates with CAP2 monomer and is aberrantly localized in spines. Taken together, these results provide novel insights into structural plasticity mechanisms that are defective in AD.

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Hippocampal synaptic plasticity in neurodegenerative diseases: Aß, tau and beyond

Neuroforum ◽

10.1515/nf-2017-a063 ◽

2018 ◽

Vol 24 (3) ◽

pp. A133-A141

Author(s):

Detlef Balschun ◽

Michael J. Rowan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Long Term Potentiation ◽

Hippocampal Synaptic Plasticity ◽

Term Potentiation ◽

Neurological Illnesses ◽

Early Alzheimer’S Disease ◽

Opposing Effects

Abstract The study of long-term potentiation (LTP) and long-term depression (LTD) in disease models provides essential mechanistic insight into synaptic dysfunction and remodelling in many neuropsychiatric and neurological illnesses. The ability of misfolded forms of the two key proteins of Alzheimer’s disease, amyloid ß (Aß) and the microtubule binding tau to disrupt hippocampal synaptic plasticity, engender highly sensitive litmus tests of impending synaptic failure and subsequent structural pathology. Many transgenic and injection-induced rodent models show rapid and persistent inhibition of LTP, and sometimes opposing effects of Aß and tau on LTD. Intriguingly, both intracellular and extracellular actions of these proteins are implicated. Both directly targeting these proteins and abrogating their synaptotoxic actions are being explored to redress the insidious shift from physiological to pathological plasticity in early Alzheimer’s disease.

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Emphasizing roles of BDNF promoters and inducers in Alzheimer's disease for improving impaired cognition and memory

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2021-0182 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Madhuparna Banerjee ◽

Rekha R. Shenoy

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurotrophic Factor ◽

Molecular Mechanisms ◽

Signal Transduction Pathway ◽

Long Term Potentiation ◽

Term Potentiation ◽

Low Levels ◽

The Brain

Abstract Brain-derived neurotrophic factor (BDNF) is a crucial neurotrophic factor adding to neurons’ development and endurance. The amount of BDNF present in the brain determines susceptibility to various neurodegenerative diseases. In Alzheimer’s disease (AD), often it is seen that low levels of BDNF are present, which primarily contributes to cognition deficit by regulating long-term potentiation (LTP) and synaptic plasticity. Molecular mechanisms underlying the synthesis, storage and release of BDNF are widely studied. New molecules are found, which contribute to the signal transduction pathway. Two important receptors of BDNF are TrkB and p75NTR. When BDNF binds to the TrkB receptor, it activates three main signalling pathways-phospholipase C, MAPK/ERK, PI3/AKT. BDNF holds an imperative part in LTP and dendritic development, which are essential for memory formation. BDNF supports synaptic integrity by influencing LTP and LTD. This action is conducted by modulating the glutamate receptors; AMPA and NMDA. This review paper discusses the aforesaid points along with inducers of BDNF. Drugs and herbals promote neuroprotection by increasing the hippocampus’ BDNF level in various disease-induced animal models for neurodegeneration. Advancement in finding pertinent molecules contributing to the BDNF signalling pathway has been discussed, along with the areas that require further research and study.

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The individual course of neuropsychiatric symptoms in people with Alzheimer's and Lewy body dementia: 12-year longitudinal cohort study

The British Journal of Psychiatry ◽

10.1192/bjp.2019.195 ◽

2019 ◽

Vol 216 (1) ◽

pp. 43-48 ◽

Cited By ~ 9

Author(s):

Audun Osland Vik-Mo ◽

Lasse Melvaer Giil ◽

Miguel Germán Borda ◽

Clive Ballard ◽

Dag Aarsland

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuropsychiatric Symptoms ◽

Personalised Medicine ◽

Lewy Bodies ◽

Lewy Body Dementia ◽

Psychotic Symptoms ◽

Primary Inclusion ◽

The Individual

IntroductionUnderstanding the natural course of neuropsychiatric symptoms (NPS) in dementia is important for planning patient care and trial design, but few studies have described the long-term course of NPS in individuals.MethodPrimary inclusion of 223 patients with suspected mild dementia from general practice were followed by annual assessment, including the Neuropsychiatric Inventory (NPI), for up to 12 years. Total and item NPI scores were classified as stable, relapsing, single episodic or not present based on 4.96 (s.d. 2.3) observations (98% completeness of longitudinal data) for 113 patients with Alzheimer's disease and 84 patients with LBD (68 dementia with Lewy bodies and 16 Parkinson's disease dementia).ResultsWe found that 80% had stable NPI total ≥1, 50% had stable modest NPI total ≥12 and 25% had stable NPI total ≥24 scores. Very severe NPS (≥48) were mostly single episodes, but 8% of patients with Alzheimer's disease had stable severe NPS. Patients with Alzheimer's disease and the highest 20% NPI total scores had a more stable or relapsing course of four key symptoms: aberrant motor behaviour, aggression/agitation, delusions and irritability (odds ratio 55, P < 0.001). This was not seen in LBD. Finally, 57% of patients with Alzheimer's disease and 84% of patients with LBD had reoccurring psychotic symptoms.ConclusionsWe observed a highly individual course of NPS, with most presenting as a single episode or relapsing; a stable course was less common, especially in LBD. These findings demonstrate the importance of an individualised approach (i.e. personalised medicine) in dementia care.

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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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