Progranulin protects against amyloid beta deposition and toxicity in Alzheimer's disease mouse models

Minami, S. Sakura (author)

Min, Sang-Won (author)

Krabbe, Grietje (author)

Wang, Chao (author)

Zhou, Yungui (author)

Asgarov, Rustam (author): Stockholms universitet,Institutionen för neurokemi

Li, Yaqiao (author)

Martens, Lauren H. (author)

Elia, Lisa P. (author)

Ward, Michael E. (author)

Mucke, Lennart (author)

Farese, Robert V. (author)

Gan, Li (author)

(creator_code:org_t)

2014-09-28
2014
English.
In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 20:10, s. 1157-1164

Related links:: https://europepmc.or...; show more...; https://urn.kb.se/re...; https://doi.org/10.1...; show less...

Abstract Subject headings

Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid beta (A beta) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. A beta plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against A beta toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against A beta deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.

By the author/editor: Minami, S. Sakur ...; Min, Sang-Won; Krabbe, Grietje; Wang, Chao; Zhou, Yungui; Asgarov, Rustam; show more...; Li, Yaqiao; Martens, Lauren ...; Elia, Lisa P.; Ward, Michael E.; Mucke, Lennart; Farese, Robert V ...; Gan, Li; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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