Suppressing aberrant phospholipase D1 signaling in 3xTg Alzheimer’s disease mouse model promotes synaptic resilience

Krystyn Z. Bourne, Chandramouli Natarajan, Carlos X.Medina Perez, Batbayar Tumurbaatar, Giulio Taglialatela, Balaji Krishnan

Research output: Contribution to journalArticle

Abstract

Current approaches in treatment of Alzheimer’s disease (AD) is focused on early stages of cognitive decline. Identifying therapeutic targets that promote synaptic resilience during early stages may prevent progressive memory deficits by preserving memory mechanisms. We recently reported that the inducible isoform of phospholipase D (PLD1) was significantly increased in synaptosomes from post-mortem AD brains compared to age-matched controls. Using mouse models, we reported that the aberrantly elevated neuronal PLD1 is key for oligomeric amyloid driven synaptic dysfunction and underlying memory deficits. Here, we demonstrate that chronic inhibition using a well-tolerated PLD1 specific small molecule inhibitor is sufficient to prevent the progression of synaptic dysfunction during early stages in the 3xTg-AD mouse model. Firstly, we report prevention of cognitive decline in the inhibitor-treated group using novel object recognition (NOR) and fear conditioning (FC). Secondly, we provide electrophysiological assessment of better synaptic function in the inhibitor-treated group. Lastly, using Golgi staining, we report that preservation of dendritic spine integrity as one of the mechanisms underlying the action of the small molecule inhibitor. Collectively, these studies provide evidence for inhibition of PLD1 as a potential therapeutic strategy in preventing progression of cognitive decline associated with AD and related dementia.

Original languageEnglish (US)
Article number18342
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Alzheimer Disease
Memory Disorders
Phospholipase D
Dendritic Spines
Synaptosomes
Amyloid
Fear
Dementia
Protein Isoforms
Staining and Labeling
phospholipase D1
Brain
Therapeutics
Cognitive Dysfunction
Inhibition (Psychology)

ASJC Scopus subject areas

  • General

Cite this

Suppressing aberrant phospholipase D1 signaling in 3xTg Alzheimer’s disease mouse model promotes synaptic resilience. / Bourne, Krystyn Z.; Natarajan, Chandramouli; Perez, Carlos X.Medina; Tumurbaatar, Batbayar; Taglialatela, Giulio; Krishnan, Balaji.

In: Scientific reports, Vol. 9, No. 1, 18342, 01.12.2019.

Research output: Contribution to journalArticle

Bourne, Krystyn Z. ; Natarajan, Chandramouli ; Perez, Carlos X.Medina ; Tumurbaatar, Batbayar ; Taglialatela, Giulio ; Krishnan, Balaji. / Suppressing aberrant phospholipase D1 signaling in 3xTg Alzheimer’s disease mouse model promotes synaptic resilience. In: Scientific reports. 2019 ; Vol. 9, No. 1.
@article{34acb7febd124195a7600f300bc435e0,
title = "Suppressing aberrant phospholipase D1 signaling in 3xTg Alzheimer’s disease mouse model promotes synaptic resilience",
abstract = "Current approaches in treatment of Alzheimer’s disease (AD) is focused on early stages of cognitive decline. Identifying therapeutic targets that promote synaptic resilience during early stages may prevent progressive memory deficits by preserving memory mechanisms. We recently reported that the inducible isoform of phospholipase D (PLD1) was significantly increased in synaptosomes from post-mortem AD brains compared to age-matched controls. Using mouse models, we reported that the aberrantly elevated neuronal PLD1 is key for oligomeric amyloid driven synaptic dysfunction and underlying memory deficits. Here, we demonstrate that chronic inhibition using a well-tolerated PLD1 specific small molecule inhibitor is sufficient to prevent the progression of synaptic dysfunction during early stages in the 3xTg-AD mouse model. Firstly, we report prevention of cognitive decline in the inhibitor-treated group using novel object recognition (NOR) and fear conditioning (FC). Secondly, we provide electrophysiological assessment of better synaptic function in the inhibitor-treated group. Lastly, using Golgi staining, we report that preservation of dendritic spine integrity as one of the mechanisms underlying the action of the small molecule inhibitor. Collectively, these studies provide evidence for inhibition of PLD1 as a potential therapeutic strategy in preventing progression of cognitive decline associated with AD and related dementia.",
author = "Bourne, {Krystyn Z.} and Chandramouli Natarajan and Perez, {Carlos X.Medina} and Batbayar Tumurbaatar and Giulio Taglialatela and Balaji Krishnan",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41598-019-54974-6",
language = "English (US)",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Suppressing aberrant phospholipase D1 signaling in 3xTg Alzheimer’s disease mouse model promotes synaptic resilience

AU - Bourne, Krystyn Z.

AU - Natarajan, Chandramouli

AU - Perez, Carlos X.Medina

AU - Tumurbaatar, Batbayar

AU - Taglialatela, Giulio

AU - Krishnan, Balaji

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Current approaches in treatment of Alzheimer’s disease (AD) is focused on early stages of cognitive decline. Identifying therapeutic targets that promote synaptic resilience during early stages may prevent progressive memory deficits by preserving memory mechanisms. We recently reported that the inducible isoform of phospholipase D (PLD1) was significantly increased in synaptosomes from post-mortem AD brains compared to age-matched controls. Using mouse models, we reported that the aberrantly elevated neuronal PLD1 is key for oligomeric amyloid driven synaptic dysfunction and underlying memory deficits. Here, we demonstrate that chronic inhibition using a well-tolerated PLD1 specific small molecule inhibitor is sufficient to prevent the progression of synaptic dysfunction during early stages in the 3xTg-AD mouse model. Firstly, we report prevention of cognitive decline in the inhibitor-treated group using novel object recognition (NOR) and fear conditioning (FC). Secondly, we provide electrophysiological assessment of better synaptic function in the inhibitor-treated group. Lastly, using Golgi staining, we report that preservation of dendritic spine integrity as one of the mechanisms underlying the action of the small molecule inhibitor. Collectively, these studies provide evidence for inhibition of PLD1 as a potential therapeutic strategy in preventing progression of cognitive decline associated with AD and related dementia.

AB - Current approaches in treatment of Alzheimer’s disease (AD) is focused on early stages of cognitive decline. Identifying therapeutic targets that promote synaptic resilience during early stages may prevent progressive memory deficits by preserving memory mechanisms. We recently reported that the inducible isoform of phospholipase D (PLD1) was significantly increased in synaptosomes from post-mortem AD brains compared to age-matched controls. Using mouse models, we reported that the aberrantly elevated neuronal PLD1 is key for oligomeric amyloid driven synaptic dysfunction and underlying memory deficits. Here, we demonstrate that chronic inhibition using a well-tolerated PLD1 specific small molecule inhibitor is sufficient to prevent the progression of synaptic dysfunction during early stages in the 3xTg-AD mouse model. Firstly, we report prevention of cognitive decline in the inhibitor-treated group using novel object recognition (NOR) and fear conditioning (FC). Secondly, we provide electrophysiological assessment of better synaptic function in the inhibitor-treated group. Lastly, using Golgi staining, we report that preservation of dendritic spine integrity as one of the mechanisms underlying the action of the small molecule inhibitor. Collectively, these studies provide evidence for inhibition of PLD1 as a potential therapeutic strategy in preventing progression of cognitive decline associated with AD and related dementia.

UR - http://www.scopus.com/inward/record.url?scp=85075998916&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075998916&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-54974-6

DO - 10.1038/s41598-019-54974-6

M3 - Article

C2 - 31797996

AN - SCOPUS:85075998916

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 18342

ER -