INVESTIGADORES
SAAVEDRA Maria Lucila
artículos
Título:
β-amyloid inhibits protein prenylation and induces cholesterol sequestration by impairing SREBP-2 cleavage.
Autor/es:
MOHAMED A; SAAVEDRA L; DI PARDO A; SIPIONE S; ELENA POSSE DE CHAVES
Revista:
JOURNAL OF NEUROSCIENCE
Editorial:
SOC NEUROSCIENCE
Referencias:
Lugar: Washington; Año: 2012 vol. 32 p. 6490 - 6500
ISSN:
0270-6474
Resumen:
Accumulation
of β-amyloid (Aβ) inside brain neurons is an early
and crucial event in Alzheimer´s disease (AD). Studies in brains of AD patients
and mice models of AD suggested that cholesterol homeostasis is altered in
neurons that accumulate Aβ. Here we directly investigated the role of intracellular oligomeric Aβ(42) (oAβ(42)) in neuronal cholesterol homeostasis. We
report that oAβ(42)
induces cholesterol sequestration without increasing cellular cholesterol mass.
Several features of AD, such as endosomal abnormalities, brain accumulation of
Aβ and neurofibrillary
tangles, and influence of apolipoprotein E genotype, are also present in
Niemann-Pick type C, a disease characterized by impairment of intracellular
cholesterol trafficking. These common features and data presented here suggest
that a pathological mechanism involving abnormal cholesterol trafficking could
take place in AD. Cholesterol sequestration in Aβ-treated neurons results from impairment of
intracellular cholesterol trafficking secondary to inhibition of protein
prenylation. oAβ(42)
reduces sterol regulatory element-binding protein-2 (SREBP-2) cleavage, causing
decrease of protein prenylation. Inhibition of protein prenylation represents a
mechanism of oAβ(42)-induced
neuronal death. Supply of the isoprenoid geranylgeranyl pyrophosphate to oAβ(42)-treated neurons recovers normal
protein prenylation, reduces cholesterol sequestration, and prevents Aβ-induced neurotoxicity. Significant
to AD, reduced levels of protein prenylation are present in the cerebral cortex
of the TgCRND8 mouse model. In conclusion, we demonstrate a significant
inhibitory effect of Aβ
on protein prenylation and identify SREBP-2 as a target of oAβ(42), directly linking Aβ to cholesterol homeostasis
impairment.