Imbalance in the response of pre- and post-synaptic components to amyloidopathy

Jackson, Jeffrey A.; Stephen, Terri‐Leigh; Tamagnini, Francesco; Piegsa, Judith; Sung, Katherine; Harvey, Joshua; Oliver-Evans, Alice; Murray, Tracey K.; Ahmed, Zeshan; Hutton, Michael; Randall, Andrew; O’Neill, Martin J.

doi:10.1101/599399

Cited by 2 publications

(2 citation statements)

References 36 publications

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“…Surprisingly, we found that presynaptic structures harboring VGluT1 are reduced in the visual cortex of hAPP mice. This finding is consistent with a recent study showing reduced bouton density but unaltered postsynaptic spine density in the barrel cortex of the same mouse model [93]. Furthermore, .…”

Section: Discussionsupporting

confidence: 93%

Functional connectivity favors aberrant visual network c-Fos expression accompanied by cortical synapse loss in a mouse model of Alzheimer’s disease

L’Esperance

McGhee

Davidson

et al. 2023

Preprint

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Hyperactivity is observed in early Alzheimers disease (AD) in multiple brain regions, including the visual cortex. We recently found that the postsynaptic structures favor visual cortex hyperactivity, which disrupts functional connectivity and leads to visual recognition memory deficits in a mouse AD model. It is unclear whether presynaptic structures also favor hyperactivity and whether hyperactivity depends on the target or source of presynaptic terminals. In addition, it is not well understood whether the functional connectivity of brain regions under nonpathological conditions predicts their hyperactivity in amyloid pathology. We used c-Fos immunolabeling under resting state conditions to map brain-wide neural activity and performed network analysis. We also quantified excitatory and inhibitory presynaptic terminals in hyperactive and non-hyperactive brain regions.We found that hyperactivity in the visual network originates in the cortex, and brain regions highly connected to the primary visual cortex in nonpathological conditions tend to be hyperactive in amyloid pathology. Immunolabeling presynaptic terminals from subcortical and cortical neurons show that the source rather than the target brain regions determine the vulnerability of synapses. Furthermore, we observed a reduction in presynaptic structures selectively in the hyperactive region, indicating presynaptic changes are unfavorable to hyperactivity. Brain regions with higher functional connectivity under nonpathological conditions are vulnerable to hyperactivity in amyloid pathology. Furthermore, presynapse loss may serve as an adaptation to maintain neuronal activity homeostasis.

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Section: Discussionsupporting

confidence: 93%

Functional connectivity favors aberrant visual network c-Fos expression accompanied by cortical synapse loss in a mouse model of Alzheimer’s disease

L’Esperance

McGhee

Davidson

et al. 2023

Preprint

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show abstract

“…Images were taken on Leica SP8 3 × STED Confocal and processed with ImageJ. In some instances (Supplemental Figure S6B) brain tissue was subjected to clearing with X‐Clarity technology (Logos Biosystems) as described in 32 . Images for 3D reconstruction were acquired on Nikon A1R HD Upright Multi‐Photon/Confocal microscope.…”

Section: Methodsmentioning

confidence: 99%

Antibody screening using a human iPSC‐based blood‐brain barrier model identifies antibodies that accumulate in the CNS

et al. 2020

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Drug delivery across the blood‐brain barrier (BBB) remains a significant obstacle for the development of neurological disease therapies. The low penetration of blood‐borne therapeutics into the brain can oftentimes be attributed to the restrictive nature of the brain microvascular endothelial cells (BMECs) that comprise the BBB. One strategy beginning to be successfully leveraged is the use of endogenous receptor‐mediated transcytosis (RMT) systems as a means to shuttle a targeted therapeutic into the brain. Limitations of known RMT targets and their cognate targeting reagents include brain specificity, brain uptake levels, and off‐target effects, driving the search for new and potentially improved brain targeting reagent‐RMT pairs. To this end, we deployed human‐induced pluripotent stem cell (iPSC)‐derived BMEC‐like cells as a model BBB substrate on which to mine for new RMT‐targeting antibody pairs. A nonimmune, human single‐chain variable fragment (scFv) phage display library was screened for binding, internalization, and transcytosis across iPSC‐derived BMECs. Lead candidates exhibited binding and internalization into BMECs as well as binding to both human and mouse BBB in brain tissue sections. Antibodies targeted the murine BBB after intravenous administration with one particular clone, 46.1‐scFv, exhibiting a 26‐fold increase in brain accumulation (8.1 nM). Moreover, clone 46.1‐scFv was found to associate with postvascular, parenchymal cells, indicating its successful receptor‐mediated transport across the BBB. Such a new BBB targeting ligand could enhance the transport of therapeutic molecules into the brain.

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Imbalance in the response of pre- and post-synaptic components to amyloidopathy

Cited by 2 publications

References 36 publications

Functional connectivity favors aberrant visual network c-Fos expression accompanied by cortical synapse loss in a mouse model of Alzheimer’s disease

Functional connectivity favors aberrant visual network c-Fos expression accompanied by cortical synapse loss in a mouse model of Alzheimer’s disease

Antibody screening using a human iPSC‐based blood‐brain barrier model identifies antibodies that accumulate in the CNS

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