Pim1 inhibition as a novel therapeutic strategy for Alzheimer’s disease
Identifieur interne : 000C84 ( Main/Exploration ); précédent : 000C83; suivant : 000C85Pim1 inhibition as a novel therapeutic strategy for Alzheimer’s disease
Auteurs : Ramon Velazquez [États-Unis] ; Darren M. Shaw [États-Unis] ; Antonella Caccamo [États-Unis] ; Salvatore Oddo [États-Unis]Source :
- Molecular Neurodegeneration [ 1750-1326 ] ; 2016.
Abstract
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.
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.
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.
Url:
DOI: 10.1186/s13024-016-0118-z
PubMed: 27412291
PubMed Central: 4944476
Affiliations:
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Tyler Street, Tempe, AZ 85287-5001 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Arizona</region></placeName><wicri:cityArea>Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, 727 E. Tyler Street, Tempe</wicri:cityArea></affiliation></author><author><name sortKey="Shaw, Darren M" sort="Shaw, Darren M" uniqKey="Shaw D" first="Darren M." last="Shaw">Darren M. Shaw</name><affiliation wicri:level="2"><nlm:aff id="Aff1">Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, 727 E. Tyler Street, Tempe, AZ 85287-5001 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Arizona</region></placeName><wicri:cityArea>Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, 727 E. Tyler Street, Tempe</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff2">School of Life Sciences, Arizona State University, Tempe, AZ 85287 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Arizona</region></placeName><wicri:cityArea>School of Life Sciences, Arizona State University, Tempe</wicri:cityArea></affiliation></author><author><name sortKey="Caccamo, Antonella" sort="Caccamo, Antonella" uniqKey="Caccamo A" first="Antonella" last="Caccamo">Antonella Caccamo</name><affiliation wicri:level="2"><nlm:aff id="Aff1">Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, 727 E. Tyler Street, Tempe, AZ 85287-5001 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Arizona</region></placeName><wicri:cityArea>Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, 727 E. Tyler Street, Tempe</wicri:cityArea></affiliation></author><author><name sortKey="Oddo, Salvatore" sort="Oddo, Salvatore" uniqKey="Oddo S" first="Salvatore" last="Oddo">Salvatore Oddo</name><affiliation wicri:level="2"><nlm:aff id="Aff1">Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, 727 E. Tyler Street, Tempe, AZ 85287-5001 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Arizona</region></placeName><wicri:cityArea>Neurodegenerative Disease Research Center, Biodesign Institute, School of Life Sciences, Arizona State University, 727 E. Tyler Street, Tempe</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff2">School of Life Sciences, Arizona State University, Tempe, AZ 85287 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Arizona</region></placeName><wicri:cityArea>School of Life Sciences, Arizona State University, Tempe</wicri:cityArea></affiliation></author></analytic><series><title level="j">Molecular Neurodegeneration</title><idno type="eISSN">1750-1326</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>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.</p></sec><sec><title>Results</title><p>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 Aβ<sub>40</sub> and Aβ<sub>42</sub> levels, as well as a 45.2 % reduction in Aβ<sub>42</sub> 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.</p></sec><sec><title>Conclusion</title><p>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.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Laferla, Fm" uniqKey="Laferla F">FM LaFerla</name></author><author><name sortKey="Oddo, S" uniqKey="Oddo S">S Oddo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Querfurth, Hw" uniqKey="Querfurth H">HW Querfurth</name></author><author><name sortKey="Laferla, Fm" uniqKey="Laferla F">FM LaFerla</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Alzheimer, A" uniqKey="Alzheimer A">A Alzheimer’s</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moll, L" uniqKey="Moll L">L Moll</name></author><author><name sortKey="El Ami, T" uniqKey="El Ami T">T 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