Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits

Smita Majumder, Arlan Richardson, Randy Strong, Salvatore - Oddo

Research output: Contribution to journalArticle

204 Citations (Scopus)

Abstract

Previous studies have shown that inducing autophagy ameliorates early cognitive deficits associated with the build-up of soluble amyloid-β (Aβ). However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble Aβ and tau represent toxic species in Alzheimer's disease (AD) pathogenesis, there is well documented evidence that plaques and tangles also are detrimental to normal brain function. Thus, it is critical to assess the effects of inducing autophagy in an animal model with established plaques and tangles. Here we show that rapamycin, when given prophylactically to 2-month-old 3xTg-AD mice throughout their life, induces autophagy and significantly reduces plaques, tangles and cognitive deficits. In contrast, inducing autophagy in 15-month-old 3xTg-AD mice, which have established plaques and tangles, has no effects on AD-like pathology and cognitive deficits. In conclusion, we show that autophagy induction via rapamycin may represent a valid therapeutic strategy in AD when administered early in the disease progression.

Original languageEnglish (US)
Article numbere25416
JournalPLoS One
Volume6
Issue number9
DOIs
StatePublished - Sep 28 2011
Externally publishedYes

Fingerprint

autophagy
Autophagy
Sirolimus
Alzheimer disease
Alzheimer Disease
Poisons
mice
Pathology
amyloid
Amyloid
disease course
Disease Progression
Brain
Animals
pathogenesis
Animal Models
animal models
brain
therapeutics

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. / Majumder, Smita; Richardson, Arlan; Strong, Randy; Oddo, Salvatore -.

In: PLoS One, Vol. 6, No. 9, e25416, 28.09.2011.

Research output: Contribution to journalArticle

@article{7bd7f811e46941469f755a96c2089bac,
title = "Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits",
abstract = "Previous studies have shown that inducing autophagy ameliorates early cognitive deficits associated with the build-up of soluble amyloid-β (Aβ). However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble Aβ and tau represent toxic species in Alzheimer's disease (AD) pathogenesis, there is well documented evidence that plaques and tangles also are detrimental to normal brain function. Thus, it is critical to assess the effects of inducing autophagy in an animal model with established plaques and tangles. Here we show that rapamycin, when given prophylactically to 2-month-old 3xTg-AD mice throughout their life, induces autophagy and significantly reduces plaques, tangles and cognitive deficits. In contrast, inducing autophagy in 15-month-old 3xTg-AD mice, which have established plaques and tangles, has no effects on AD-like pathology and cognitive deficits. In conclusion, we show that autophagy induction via rapamycin may represent a valid therapeutic strategy in AD when administered early in the disease progression.",
author = "Smita Majumder and Arlan Richardson and Randy Strong and Oddo, {Salvatore -}",
year = "2011",
month = "9",
day = "28",
doi = "10.1371/journal.pone.0025416",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits

AU - Majumder, Smita

AU - Richardson, Arlan

AU - Strong, Randy

AU - Oddo, Salvatore -

PY - 2011/9/28

Y1 - 2011/9/28

N2 - Previous studies have shown that inducing autophagy ameliorates early cognitive deficits associated with the build-up of soluble amyloid-β (Aβ). However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble Aβ and tau represent toxic species in Alzheimer's disease (AD) pathogenesis, there is well documented evidence that plaques and tangles also are detrimental to normal brain function. Thus, it is critical to assess the effects of inducing autophagy in an animal model with established plaques and tangles. Here we show that rapamycin, when given prophylactically to 2-month-old 3xTg-AD mice throughout their life, induces autophagy and significantly reduces plaques, tangles and cognitive deficits. In contrast, inducing autophagy in 15-month-old 3xTg-AD mice, which have established plaques and tangles, has no effects on AD-like pathology and cognitive deficits. In conclusion, we show that autophagy induction via rapamycin may represent a valid therapeutic strategy in AD when administered early in the disease progression.

AB - Previous studies have shown that inducing autophagy ameliorates early cognitive deficits associated with the build-up of soluble amyloid-β (Aβ). However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble Aβ and tau represent toxic species in Alzheimer's disease (AD) pathogenesis, there is well documented evidence that plaques and tangles also are detrimental to normal brain function. Thus, it is critical to assess the effects of inducing autophagy in an animal model with established plaques and tangles. Here we show that rapamycin, when given prophylactically to 2-month-old 3xTg-AD mice throughout their life, induces autophagy and significantly reduces plaques, tangles and cognitive deficits. In contrast, inducing autophagy in 15-month-old 3xTg-AD mice, which have established plaques and tangles, has no effects on AD-like pathology and cognitive deficits. In conclusion, we show that autophagy induction via rapamycin may represent a valid therapeutic strategy in AD when administered early in the disease progression.

UR - http://www.scopus.com/inward/record.url?scp=80053243942&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053243942&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0025416

DO - 10.1371/journal.pone.0025416

M3 - Article

C2 - 21980451

AN - SCOPUS:80053243942

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 9

M1 - e25416

ER -