scholarly journals 2459 Hippocampal network disruption in early amyloid pathology

2018 ◽  
Vol 2 (S1) ◽  
pp. 14-14
Author(s):  
Adam Caccavano ◽  
Stefano Vicini
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Brain Slices ◽  
Synaptic Activity ◽  
Network Activity ◽  
Pharmacological Intervention ◽  
Functional Assay ◽  
Hippocampal Network ◽  
Network Disruption

OBJECTIVES/SPECIFIC AIMS: We aim to show that amyloid accumulation in an animal model of Alzheimer’s disease leads to a preferential disruption of inhibitory parvalbumin-expressing interneurons, and the peri-neuronal nets that surround them, resulting in downstream network alterations to potentially explain early mechanisms of memory impairment in the disease. METHODS/STUDY POPULATION: We employ the 5xFAD mouse model of familial Alzheimer’s disease crossed with transgenic mouse lines which fluoresce red or green in specific neuronal populations. We conducted immunostaining and immunoblotting in amyloid accumulating animals compared with healthy littermate control. Future experiments will be performed in human postmortem tissue to translate these results from mouse model to the human population. Electrophysiological recordings from acute mouse brain slices were conducted as a functional assay. RESULTS/ANTICIPATED RESULTS: Preliminary results indicate that PNNs are disrupted and that activity-associated levels of PV are reduced. Both inhibitory PV and excitatory pyramidal cell populations exhibit altered spiking and synaptic activity during sharp wave ripple events. DISCUSSION/SIGNIFICANCE OF IMPACT: By elucidating the specific neuronal sub-type that is responsible for hippocampal network disruption, future studies could attempt a targeted optogenetic or pharmacological intervention to restore network activity important for memory consolidation.

scholarly journals 3177 Determining mechanisms underlying hippocampal network disruption in early amyloid pathology

2019 ◽  
Vol 3 (s1) ◽  
pp. 103-104
Author(s):  
Adam Caccavano ◽  
P. Lorenzo Bozzelli ◽  
Katherine Conant ◽  
Stefano Vicini
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Extracellular Matrix ◽  
Mouse Model ◽  
Memory Consolidation ◽  
Network Activity ◽  
Health Crisis ◽  
Memory Disruption ◽  
Hippocampal Network ◽  
Network Disruption

OBJECTIVES/SPECIFIC AIMS: Alzheimer’s disease (AD) is the leading cause of dementia, and a rapidly growing public health crisis as life expectancy increases. Two hallmark symptoms of the disease are memory impairment and the pathological accumulation of amyloid beta protein. The hippocampus is a brain region critical for the consolidation of new memories, and one of the first regions in which amyloid accumulation is observed. Our lab and others have observed a disruption to hippocampal network activity that is critical for memory consolidation in amyloid-accumulating mice. However, the mechanisms and neuronal micro-circuitry underlying this disruption are under-explored, a critical gap that warrants exploration if we are to understand memory disruption in the disease. In this study we have investigated the hypothesis that a preferential disruption to inhibitory PV neurons and the extracellular matrix that surrounds this cell type underlies downstream network alterations. METHODS/STUDY POPULATION: We have employed the 5xFAD mouse model of familial Alzheimer’s disease crossed with transgenic lines that selectively fluoresce in different neuronal sub-types. In a multi-modal approach, we have investigated behavioral, electrophysiological, and biochemical alterations between 3-month-old amyloid-accumulating 5xFAD mice and littermate controls. RESULTS/ANTICIPATED RESULTS: We observe a 35% increase in the incidence of synchronous hippocampal oscillations known as sharp wave ripples (SWRs) in amyloid-accumulating mice versus littermate controls (n = 28, p = 0.01), as well as a 95% increase in the power of slow gamma oscillations (p = 0.002). This hyperexcitability of the hippocampal network is correlated with an impairment in hippocampal-dependent memory, assayed with the Barnes Maze, a behavioral test of spatial memory (172% increase in latency to find escape hole, n = 8, p = 0.01). To elucidate the micro-circuitry that underlies this network disruption, we have investigated the integrity of peri-neuronal nets (PNNs), part of the extracellular matrix of proteins that preferentially ensheathe inhibitory PV neurons and support their function. We observe a 60% decrease in intensity of PNNs (n = 5, p = 0.005), suggesting PNN integrity is impaired in amyloid-accumulating mice. Ongoing experiments into the activity and synaptic input to both inhibitory PV and excitatory pyramidal neurons seek to determine the effects of this PNN disruption on downstream micro-circuitry. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings suggest that a preferential impairment to PNNs and inhibitory PV cells underlie hippocampal hyperexcitability in a mouse model of AD. As hippocampal network activity is critical for memory consolidation, these effects contribute to our understanding of memory disruption during early disease progression, which has been poorly understood to date. These findings provide a foundation for future in vivo studies employing optogenetic stimulation to this neuronal sub-type, to determine if restoring physiological network balance can ameliorate memory decline.

scholarly journals Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease

2019 ◽  
Vol 25 (12) ◽  
pp. 3380-3398 ◽  
Author(s):  
Sara Hijazi ◽  
Tim S. Heistek ◽  
Philip Scheltens ◽  
Ulf Neumann ◽  
Derya R. Shimshek ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Neuronal Network ◽  
Pyramidal Cells ◽  
Network Activity ◽  
Inhibitory Input ◽  
Model Of Alzheimer’S Disease ◽  
Entry Points ◽  
Interneuron Activity

AbstractNeuronal network dysfunction is increasingly recognized as an early symptom in Alzheimer’s disease (AD) and may provide new entry points for diagnosis and intervention. Here, we show that amyloid-beta-induced hyperexcitability of hippocampal inhibitory parvalbumin (PV) interneurons importantly contributes to neuronal network dysfunction and memory impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We demonstrate that hippocampal PV interneurons become hyperexcitable at ~16 weeks of age, when no changes are observed yet in the intrinsic properties of pyramidal cells. This hyperexcitable state of PV interneurons coincides with increased inhibitory transmission onto hippocampal pyramidal neurons and deficits in spatial learning and memory. We show that treatment aimed at preventing PV interneurons from becoming hyperexcitable is sufficient to restore PV interneuron properties to wild-type levels, reduce inhibitory input onto pyramidal cells, and rescue memory deficits in APP/PS1 mice. Importantly, we demonstrate that early intervention aimed at restoring PV interneuron activity has long-term beneficial effects on memory and hippocampal network activity, and reduces amyloid plaque deposition, a hallmark of AD pathology. Taken together, these findings suggest that early treatment of PV interneuron hyperactivity might be clinically relevant in preventing memory decline and delaying AD progression.

scholarly journals Early Onset of Hypersynchronous Network Activity and Expression of a Marker of Chronic Seizures in the Tg2576 Mouse Model of Alzheimer’s Disease

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0119910 ◽  
Author(s):  
Charlotte Bezzina ◽  
Laure Verret ◽  
Cécile Juan ◽  
Jessica Remaud ◽  
Hélène Halley ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Early Onset ◽  
Network Activity ◽  
Tg2576 Mouse ◽  
Model Of Alzheimer’S Disease

scholarly journals miR-135a-5p mediates memory and synaptic impairments via the Rock2/Adducin1 signaling pathway in a mouse model of Alzheimer’s disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kai Zheng ◽  
Fan Hu ◽  
Yang Zhou ◽  
Juan Zhang ◽  
Jie Zheng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Signaling Pathway ◽  
Hippocampal Neurons ◽  
Therapeutic Strategy ◽  
Memory Deficits ◽  
Synaptic Activity ◽  
Memory Impairments ◽  
Model Of Alzheimer’S Disease

AbstractAberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer’s disease (AD), but most abnormally expressed miRNAs found in AD are not regulated by synaptic activity. Here we report that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in a mouse model of AD. miR-135a-5p levels are significantly reduced in excitatory hippocampal neurons of AD model mice. This decrease is tau dependent and mediated by Foxd3. Inhibition of miR-135a-5p leads to synaptic disorder and memory impairments. Furthermore, excess Rock2 levels caused by loss of miR-135a-5p plays an important role in the synaptic disorder of AD via phosphorylation of Ser726 on adducin 1 (Add1). Blocking the phosphorylation of Ser726 on Add1 with a membrane-permeable peptide effectively rescues the memory impairments in AD mice. Taken together, these findings demonstrate that synaptic-related miR-135a-5p mediates synaptic/memory deficits in AD via the Rock2/Add1 signaling pathway, illuminating a potential therapeutic strategy for AD.

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