Dataset Information

Inhibition of Polo-like kinase 2 ameliorates pathogenesis in Alzheimer's disease model mice.

ABSTRACT: Alzheimer disease (AD) is a neurodegenerative disorder characterized by pathological hallmarks of neurofibrillary tangles and amyloid plaques. The plaques are formed by aggregation and accumulation of amyloid ? (A?), a cleavage fragment of amyloid precursor protein (APP). Enhanced neuronal activity and seizure events are frequently observed in AD, and elevated synaptic activity promotes A? production. However, the mechanisms that link synaptic hyperactivity to APP processing and AD pathogenesis are not well understood. We previously found that Polo-like kinase 2 (Plk2), a homeostatic repressor of neuronal overexcitation, promotes APP ?-processing in vitro. Here, we report that Plk2 stimulates A? production in vivo, and that Plk2 levels are elevated in a spatiotemporally regulated manner in brains of AD mouse models and human AD patients. Genetic disruption of Plk2 kinase function reduces plaque deposits and activity-dependent A? production. Furthermore, pharmacological Plk2 inhibition hinders A? formation, synapse loss, and memory decline in an AD mouse model. Thus, Plk2 links synaptic overactivity to APP ?-processing, A? production, and disease-relevant phenotypes in vivo, suggesting that Plk2 may be a potential target for AD therapeutics.

SUBMITTER: Lee JS

PROVIDER: S-EPMC6629081 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inhibition of Polo-like kinase 2 ameliorates pathogenesis in Alzheimer's disease model mice.

Lee Ji Soo JS Lee Yeunkum Y André Emily A EA Lee Kea Joo KJ Nguyen Thien T Feng Yang Y Jia Nuo N Harris Brent T BT Burns Mark P MP Pak Daniel T S DTS

PloS one 20190715 7

Alzheimer disease (AD) is a neurodegenerative disorder characterized by pathological hallmarks of neurofibrillary tangles and amyloid plaques. The plaques are formed by aggregation and accumulation of amyloid β (Aβ), a cleavage fragment of amyloid precursor protein (APP). Enhanced neuronal activity and seizure events are frequently observed in AD, and elevated synaptic activity promotes Aβ production. However, the mechanisms that link synaptic hyperactivity to APP processing and AD pathogenesis ...[more]

PMID: 31306446

Similar Datasets

Project description:Excessive mitochondrial fission is a prominent early event and contributes to mitochondrial dysfunction, synaptic failure, and neuronal cell death in the progression of Alzheimer's disease (AD). However, it remains to be determined whether inhibition of excessive mitochondrial fission is beneficial in mammal models of AD. To determine whether dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fragmentation, can be a disease-modifying therapeutic target for AD, we examined the effects of Drp1 inhibitor on mitochondrial and synaptic dysfunctions induced by oligomeric amyloid-? (A?) in neurons and neuropathology and cognitive functions in A? precursor protein/presenilin 1 double-transgenic AD mice. Inhibition of Drp1 alleviates mitochondrial fragmentation, loss of mitochondrial membrane potential, reactive oxygen species production, ATP reduction, and synaptic depression in A?-treated neurons. Furthermore, Drp1 inhibition significantly improves learning and memory and prevents mitochondrial fragmentation, lipid peroxidation, BACE1 expression, and A? deposition in the brain in the AD model. These results provide evidence that Drp1 plays an important role in A?-mediated and AD-related neuropathology and in cognitive decline in an AD animal model. Therefore, inhibiting excessive Drp1-mediated mitochondrial fission may be an efficient therapeutic avenue for AD.SIGNIFICANCE STATEMENT Mitochondrial fission relies on the evolutionary conserved dynamin-related protein 1 (Drp1). Drp1 activity and mitochondria fragmentation are significantly elevated in the brains of sporadic Alzheimer's disease (AD) cases. In the present study, we first demonstrated that the inhibition of Drp1 restored amyloid-? (A?)-mediated mitochondrial dysfunctions and synaptic depression in neurons and significantly reduced lipid peroxidation, BACE1 expression, and A? deposition in the brain of AD mice. As a result, memory deficits in AD mice were rescued by Drp1 inhibition. These results suggest that neuropathology and combined cognitive decline can be attributed to hyperactivation of Drp1 in the pathogenesis of AD. Therefore, inhibitors of excessive mitochondrial fission, such as Drp1 inhibitors, may be a new strategy for AD.

Dataset Information

Inhibition of Polo-like kinase 2 ameliorates pathogenesis in Alzheimer's disease model mice.

Publications

Inhibition of Polo-like kinase 2 ameliorates pathogenesis in Alzheimer's disease model mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure