Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression

Frontiers in Synaptic Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: March 9, 2023

The synapse has consistently been considered a vulnerable and critical target within Alzheimer’s disease, loss is, to date, one of the main biological correlates cognitive decline disease. This occurs prior neuronal with ample evidence that synaptic dysfunction precedes this, in support idea failure is crucial stage disease pathogenesis. two pathological hallmarks abnormal aggregates amyloid or tau proteins, have had demonstrable effects on physiology animal cellular models There also growing these proteins may synergistic effect neurophysiological dysfunction. Here, we review some findings alterations what know from models. First, briefly summarize human suggest synapses are altered, including how this relates network activity. Subsequently, considered, highlighting mouse pathology role play dysfunction, either isolation examining pathologies interact specifically focuses function observed models, typically measured using electrophysiology calcium imaging. Following loss, it would be impossible imagine not alter oscillatory activity brain. Therefore, discusses underpin aberrant patterns seen patients. Finally, an overview key directions considerations field covered. includes current therapeutics targeted at but methods modulate rescue patterns. Other important future avenues note include non-neuronal cell types such as astrocytes microglia, mechanisms independent will certainly continue for foreseeable future.

Language: Английский

---

Treadmill Exercise Prevents Decline in Spatial Learning and Memory in 3×Tg-AD Mice through Enhancement of Structural Synaptic Plasticity of the Hippocampus and Prefrontal Cortex

Cells, Journal Year: 2022, Volume and Issue: 11(2), P. 244 - 244

Published: Jan. 12, 2022

Alzheimer’s disease (AD) is characterized by deficits in learning and memory. A pathological feature of AD the alterations number size synapses, axon length, dendritic complexity, spine numbers hippocampus prefrontal cortex. Treadmill exercise can enhance synaptic plasticity mouse or rat models stroke, ischemia, dementia. The aim this study was to examine effects treadmill on memory, structural 3×Tg-AD mice, a model AD. Here, we show that 12 weeks beginning three-month-old mice improves spatial working memory six-month-old while non-exercise exhibited impaired To investigate potential mechanisms for exercise-induced improvement examined cortex had undergone exercise. We found led increases synapse numbers, parameters, expression synaptophysin (Syn, presynaptic marker), spines restored these parameters similar levels non-Tg control without In addition, also improved mice. Strengthening may represent mechanism which prevents decline loss

Language: Английский

---

Intranasal delivery of pro-resolving lipid mediators rescues memory and gamma oscillation impairment in AppNL-G-F/NL-G-F mice

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: March 21, 2022

Sustained microglial activation and increased pro-inflammatory signalling cause chronic inflammation neuronal damage in Alzheimer's disease (AD). Resolution of follows neutralization pathogens is a response to limit promote healing, mediated by pro-resolving lipid mediators (LMs). Since resolution impaired AD brains, we decided test if intranasal administration LMs the AppNL-G-F/NL-G-F mouse model for could resolve ameliorate pathology brain. A mixture resolvin (Rv) E1, RvD1, RvD2, maresin 1 (MaR1) neuroprotectin D1 (NPD1) was administered stimulate their respective receptors. We examined amyloid load, cognition, network oscillations, glial inflammatory factors. The treatment ameliorated memory deficits accompanied restoration gamma oscillation deficits, together with dramatic decrease activation. These findings open potential avenues therapeutic exploration AD, using non-invasive route.

Language: Английский

---

Mitochondrial hypermetabolism precedes impaired autophagy and synaptic disorganization in App knock-in Alzheimer mouse models

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(9), P. 3966 - 3981

Published: Sept. 1, 2023

Accumulation of amyloid β-peptide (Aβ) is a driver Alzheimer's disease (AD). Amyloid precursor protein (App) knock-in mouse models recapitulate AD-associated Aβ pathology, allowing elucidation downstream effects accumulation and their temporal appearance upon progression. Here we have investigated the sequential onset AD-like pathologies in AppNL-F AppNL-G-F mice by time-course transcriptome analysis hippocampus, region severely affected AD. Strikingly, energy metabolism emerged as one most significantly altered pathways already at an early stage pathology. Functional experiments isolated mitochondria from hippocampus both confirmed upregulation oxidative phosphorylation driven activity mitochondrial complexes I, IV V, associated with higher susceptibility to damage Ca2+-overload. Upon increasing pathologies, brain shifts state hypometabolism reduced abundancy presynaptic terminals. These late-stage also displayed enlarged areas abnormal synaptic vesicles autophagosomes, latter ultimately leading local autophagy impairment synapses. In summary, report that Aβ-induced App key observed AD brain, our data herein adds comprehensive understanding including dysregulated synapses timewise find new therapeutic approaches for

Language: Английский

---

Timing to be precise? An overview of spike timing-dependent plasticity, brain rhythmicity, and glial cells interplay within neuronal circuits

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(6), P. 2177 - 2188

Published: March 29, 2023

Abstract In the mammalian brain information processing and storage rely on complex coding decoding events performed by neuronal networks. These actions are based computational ability of neurons their functional engagement in assemblies where precise timing action potential firing is crucial. Neuronal circuits manage a myriad spatially temporally overlapping inputs to compute specific outputs that proposed underly memory traces formation, sensory perception, cognitive behaviors. Spike-timing-dependent plasticity (STDP) electrical rhythms suggested underlie such functions while physiological evidence assembly structures mechanisms driving both processes continues be scarce. Here, we review foundational current precision cooperative activity STDP rhythms, interactions, emerging role glial cells processes. We also provide an overview correlates discuss limitations controversies, future perspectives experimental approaches, application humans.

Language: Английский

---

Dynamic microglia alterations associate with hippocampal network impairments: A turning point in amyloid pathology progression

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 119, P. 286 - 300

Published: April 10, 2024

Alzheimer's disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of deterioration neurodegeneration remain unclear, leading to lack effective strategies prevent dementia. Recent evidence highlights the role neuroinflammation, particularly involving microglia, in onset progression. Characterizing initial phase can lead discovery new biomarkers therapeutic targets, facilitating timely interventions for treatments. We used AppNL-G-F knock-in mouse model, which resembles amyloid pathology neuroinflammatory characteristics disease, investigate transition from pre-plaque an early plaque stage with combined functional molecular approach. Our experiments show decrease power cognition-relevant hippocampal gamma oscillations during pathology, together modification fast-spiking interneuron intrinsic properties postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes synaptic function-associated pathways. Concurrently, homeostasis- inflammatory-related microglia signature genes were downregulated. Moreover, we found Iba1-positive hippocampus correlates aggregation neuronal dysfunction. Collectively, findings support hypothesis play protective stages preventing aggregation, supporting homeostasis, overall preserving oscillatory network's functionality. These results suggest alteration dynamics could be pivotal event progression potentially triggering deposition, impairment interneurons, breakdown circuitry hippocampus.

Language: Английский

---

Theta and gamma oscillatory dynamics in mouse models of Alzheimer’s disease: A path to prospective therapeutic intervention

Neuroscience & Biobehavioral Reviews, Journal Year: 2022, Volume and Issue: 136, P. 104628 - 104628

Published: March 22, 2022

Language: Английский

---

Biophysical Kv3 channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer’s

eLife, Journal Year: 2022, Volume and Issue: 11

Published: June 21, 2022

In Alzheimer’s disease (AD), a multitude of genetic risk factors and early biomarkers are known. Nevertheless, the causal responsible for initiating cognitive decline in AD remain controversial. Toxic plaques tangles correlate with progressive neuropathology, yet disruptions circuit activity emerge before their deposition models patients. Parvalbumin (PV) interneurons potential candidates dysregulating cortical excitability as they display altered action (AP) firing neighboring excitatory neurons prodromal AD. Here, we report novel mechanism PV hypoexcitability young adult familial mice. We found that biophysical modulation K v 3 channels, but not changes mRNA or protein expression, were dampened 5xFAD These + conductances could efficiently regulate near-threshold AP firing, resulting gamma-frequency-specific network hyperexcitability. Thus, ion channel alterations alone may reshape prior to expression levels. Our findings demonstrate an opportunity design class targeted therapies ameliorate hyperexcitability

Language: Английский

---

Intravenous treatment with a molecular chaperone designed against β-amyloid toxicity improves Alzheimer’s disease pathology in mouse models

Molecular Therapy, Journal Year: 2022, Volume and Issue: 31(2), P. 487 - 502

Published: Aug. 17, 2022

Attempts to treat Alzheimer's disease with immunotherapy against the β-amyloid (Aβ) peptide or enzyme inhibitors reduce Aβ production have not yet resulted in effective treatment, suggesting that alternative strategies may be useful. Here we explore possibility of targeting toxicity associated aggregation by using recombinant human (rh) Bri2 BRICHOS chaperone domain, mutated act selectively Aβ42 oligomer generation and neurotoxicity vitro. We find treatment precursor protein (App) knockin mice repeated intravenous injections rh R221E, from an age close start development disease-like pathology, improves recognition working memory, as assessed novel object Y maze tests, reduces plaque deposition activation astrocytes microglia. When was started about 4 months after pathology already established, memory improvement detected, but gliosis were reduced, substantially reduced astrocyte accumulation vicinity plaques observed. The degrees effects observed App mouse models apparently correlate amounts detected brain sections end period.

Language: Английский

---

Early Detection of Alzheimer’s Disease From Cortical and Hippocampal Local Field Potentials Using an Ensembled Machine Learning Model

IEEE Transactions on Neural Systems and Rehabilitation Engineering, Journal Year: 2023, Volume and Issue: 31, P. 2839 - 2848

Published: Jan. 1, 2023

Early diagnosis of Alzheimer's disease (AD) is a very challenging problem and has been attempted through data-driven methods in recent years. However, considering the inherent complexity decoding higher cognitive functions from spontaneous neuronal signals, these benefit incorporation multimodal data. This work proposes an ensembled machine learning model with explainability (EXML) to detect subtle patterns cortical hippocampal local field potential signals (LFPs) that can be considered as marker for AD early stage disease. The LFPs acquired healthy two types animal models (n = 10 each) using linear multielectrode probes were endorsed by electrocardiogram respiration their veracity. Feature sets generated temporal, spatial spectral domains fed into selected machine-learning each domain. Using late fusion, EXML achieved overall accuracy 99.4%. provided insights amyloid plaque deposition process 3 months onset identifying network activities. Lastly, individual ensemble found robust when evaluated randomly masking channels mimic presence artefacts.

Language: Английский

---