Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease

Ramon Velazquez, Darren M. Shaw, Antonella Caccamo, Salvatore - Oddo

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Clinically, AD is characterized by impairments of memory and cognitive functions. Accumulation of amyloid-β (Aβ) and neurofibrillary tangles are the prominent neuropathologies in patients with AD. Strong evidence indicates that an imbalance between production and degradation of key proteins contributes to the pathogenesis of AD. The mammalian target of rapamycin (mTOR) plays a key role in maintaining protein homeostasis as it regulates both protein synthesis and degradation. A key regulator of mTOR activity is the proline-rich AKT substrate 40 kDa (PRAS40), which directly binds to mTOR and reduces its activity. Notably, AD patients have elevated levels of phosphorylated PRAS40, which correlate with Aβ and tau pathologies as well as cognitive deficits. Physiologically, PRAS40 phosphorylation is regulated by Pim1, a protein kinase of the protoconcogene family. Here, we tested the effects of a selective Pim1 inhibitor (Pim1i), on spatial reference and working memory and AD-like pathology in 3xTg-AD mice. Results: We have identified a Pim1i that crosses the blood brain barrier and reduces PRAS40 phosphorylation. Pim1i-treated 3xTg-AD mice performed significantly better than their vehicle treated counterparts as well as non-transgenic mice. Additionally, 3xTg-AD Pim1i-treated mice showed a reduction in soluble and insoluble Aβ40 and Aβ42 levels, as well as a 45.2 % reduction in Aβ42 plaques within the hippocampus. Furthermore, phosphorylated tau immunoreactivity was reduced in the hippocampus of Pim1i-treated 3xTg-AD mice by 38 %. Mechanistically, these changes were linked to a significant increase in proteasome activity. Conclusion: These results suggest that reductions in phosphorylated PRAS40 levels via Pim1 inhibition reduce Aβ and Tau pathology and rescue cognitive deficits by increasing proteasome function. Given that Pim1 inhibitors are already being tested in ongoing human clinical trials for cancer, the results presented here may open a new venue of drug discovery for AD by developing more Pim1 inhibitors.

Original languageEnglish (US)
Article number52
JournalMolecular Neurodegeneration
Volume11
Issue number1
DOIs
StatePublished - Jul 13 2016

Fingerprint

Alzheimer Disease
Proline
Sirolimus
Therapeutics
Proteasome Endopeptidase Complex
Pathology
Proteolysis
Hippocampus
Inhibition (Psychology)
Phosphorylation
Neurofibrillary Tangles
Drug Discovery
Blood-Brain Barrier
Short-Term Memory
Amyloid
Neurodegenerative Diseases
Protein Kinases
Cognition
Homeostasis
Clinical Trials

Keywords

  • 3xTg-AD
  • AD
  • Aging
  • mTOR
  • Pim1 inhibitor
  • PRAS40
  • Proteasome
  • tau
  • Working memory

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease. / Velazquez, Ramon; Shaw, Darren M.; Caccamo, Antonella; Oddo, Salvatore -.

In: Molecular Neurodegeneration, Vol. 11, No. 1, 52, 13.07.2016.

Research output: Contribution to journalArticle

Velazquez, Ramon ; Shaw, Darren M. ; Caccamo, Antonella ; Oddo, Salvatore -. / Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease. In: Molecular Neurodegeneration. 2016 ; Vol. 11, No. 1.
@article{8fb21ecdd564430c944cb2e5c6a4b350,
title = "Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease",
abstract = "Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Clinically, AD is characterized by impairments of memory and cognitive functions. Accumulation of amyloid-β (Aβ) and neurofibrillary tangles are the prominent neuropathologies in patients with AD. Strong evidence indicates that an imbalance between production and degradation of key proteins contributes to the pathogenesis of AD. The mammalian target of rapamycin (mTOR) plays a key role in maintaining protein homeostasis as it regulates both protein synthesis and degradation. A key regulator of mTOR activity is the proline-rich AKT substrate 40 kDa (PRAS40), which directly binds to mTOR and reduces its activity. Notably, AD patients have elevated levels of phosphorylated PRAS40, which correlate with Aβ and tau pathologies as well as cognitive deficits. Physiologically, PRAS40 phosphorylation is regulated by Pim1, a protein kinase of the protoconcogene family. Here, we tested the effects of a selective Pim1 inhibitor (Pim1i), on spatial reference and working memory and AD-like pathology in 3xTg-AD mice. Results: We have identified a Pim1i that crosses the blood brain barrier and reduces PRAS40 phosphorylation. Pim1i-treated 3xTg-AD mice performed significantly better than their vehicle treated counterparts as well as non-transgenic mice. Additionally, 3xTg-AD Pim1i-treated mice showed a reduction in soluble and insoluble Aβ40 and Aβ42 levels, as well as a 45.2 {\%} reduction in Aβ42 plaques within the hippocampus. Furthermore, phosphorylated tau immunoreactivity was reduced in the hippocampus of Pim1i-treated 3xTg-AD mice by 38 {\%}. Mechanistically, these changes were linked to a significant increase in proteasome activity. Conclusion: These results suggest that reductions in phosphorylated PRAS40 levels via Pim1 inhibition reduce Aβ and Tau pathology and rescue cognitive deficits by increasing proteasome function. Given that Pim1 inhibitors are already being tested in ongoing human clinical trials for cancer, the results presented here may open a new venue of drug discovery for AD by developing more Pim1 inhibitors.",
keywords = "3xTg-AD, AD, Aging, Aβ, mTOR, Pim1 inhibitor, PRAS40, Proteasome, tau, Working memory",
author = "Ramon Velazquez and Shaw, {Darren M.} and Antonella Caccamo and Oddo, {Salvatore -}",
year = "2016",
month = "7",
day = "13",
doi = "10.1186/s13024-016-0118-z",
language = "English (US)",
volume = "11",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease

AU - Velazquez, Ramon

AU - Shaw, Darren M.

AU - Caccamo, Antonella

AU - Oddo, Salvatore -

PY - 2016/7/13

Y1 - 2016/7/13

N2 - Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Clinically, AD is characterized by impairments of memory and cognitive functions. Accumulation of amyloid-β (Aβ) and neurofibrillary tangles are the prominent neuropathologies in patients with AD. Strong evidence indicates that an imbalance between production and degradation of key proteins contributes to the pathogenesis of AD. The mammalian target of rapamycin (mTOR) plays a key role in maintaining protein homeostasis as it regulates both protein synthesis and degradation. A key regulator of mTOR activity is the proline-rich AKT substrate 40 kDa (PRAS40), which directly binds to mTOR and reduces its activity. Notably, AD patients have elevated levels of phosphorylated PRAS40, which correlate with Aβ and tau pathologies as well as cognitive deficits. Physiologically, PRAS40 phosphorylation is regulated by Pim1, a protein kinase of the protoconcogene family. Here, we tested the effects of a selective Pim1 inhibitor (Pim1i), on spatial reference and working memory and AD-like pathology in 3xTg-AD mice. Results: We have identified a Pim1i that crosses the blood brain barrier and reduces PRAS40 phosphorylation. Pim1i-treated 3xTg-AD mice performed significantly better than their vehicle treated counterparts as well as non-transgenic mice. Additionally, 3xTg-AD Pim1i-treated mice showed a reduction in soluble and insoluble Aβ40 and Aβ42 levels, as well as a 45.2 % reduction in Aβ42 plaques within the hippocampus. Furthermore, phosphorylated tau immunoreactivity was reduced in the hippocampus of Pim1i-treated 3xTg-AD mice by 38 %. Mechanistically, these changes were linked to a significant increase in proteasome activity. Conclusion: These results suggest that reductions in phosphorylated PRAS40 levels via Pim1 inhibition reduce Aβ and Tau pathology and rescue cognitive deficits by increasing proteasome function. Given that Pim1 inhibitors are already being tested in ongoing human clinical trials for cancer, the results presented here may open a new venue of drug discovery for AD by developing more Pim1 inhibitors.

AB - Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Clinically, AD is characterized by impairments of memory and cognitive functions. Accumulation of amyloid-β (Aβ) and neurofibrillary tangles are the prominent neuropathologies in patients with AD. Strong evidence indicates that an imbalance between production and degradation of key proteins contributes to the pathogenesis of AD. The mammalian target of rapamycin (mTOR) plays a key role in maintaining protein homeostasis as it regulates both protein synthesis and degradation. A key regulator of mTOR activity is the proline-rich AKT substrate 40 kDa (PRAS40), which directly binds to mTOR and reduces its activity. Notably, AD patients have elevated levels of phosphorylated PRAS40, which correlate with Aβ and tau pathologies as well as cognitive deficits. Physiologically, PRAS40 phosphorylation is regulated by Pim1, a protein kinase of the protoconcogene family. Here, we tested the effects of a selective Pim1 inhibitor (Pim1i), on spatial reference and working memory and AD-like pathology in 3xTg-AD mice. Results: We have identified a Pim1i that crosses the blood brain barrier and reduces PRAS40 phosphorylation. Pim1i-treated 3xTg-AD mice performed significantly better than their vehicle treated counterparts as well as non-transgenic mice. Additionally, 3xTg-AD Pim1i-treated mice showed a reduction in soluble and insoluble Aβ40 and Aβ42 levels, as well as a 45.2 % reduction in Aβ42 plaques within the hippocampus. Furthermore, phosphorylated tau immunoreactivity was reduced in the hippocampus of Pim1i-treated 3xTg-AD mice by 38 %. Mechanistically, these changes were linked to a significant increase in proteasome activity. Conclusion: These results suggest that reductions in phosphorylated PRAS40 levels via Pim1 inhibition reduce Aβ and Tau pathology and rescue cognitive deficits by increasing proteasome function. Given that Pim1 inhibitors are already being tested in ongoing human clinical trials for cancer, the results presented here may open a new venue of drug discovery for AD by developing more Pim1 inhibitors.

KW - 3xTg-AD

KW - AD

KW - Aging

KW - Aβ

KW - mTOR

KW - Pim1 inhibitor

KW - PRAS40

KW - Proteasome

KW - tau

KW - Working memory

UR - http://www.scopus.com/inward/record.url?scp=84979654242&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84979654242&partnerID=8YFLogxK

U2 - 10.1186/s13024-016-0118-z

DO - 10.1186/s13024-016-0118-z

M3 - Article

C2 - 27412291

AN - SCOPUS:84979654242

VL - 11

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

SN - 1750-1326

IS - 1

M1 - 52

ER -