Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice

Neurobiol Aging. 2006 Nov;27(11):1632-43. doi: 10.1016/j.neurobiolaging.2005.09.011. Epub 2005 Oct 19.

Abstract

Emerging evidence indicates that cholesterol metabolism affects the pathogenesis of Alzheimer's disease (AD). The LDL receptor (LDLR) is obligatory in maintaining cholesterol homeostasis in the periphery. To investigate the role of LDLR in the development of AD-like behavior and pathology, Tg2576 mice, a well-characterized transgenic mouse model of AD, with different genotypes of LDLR were generated. Here we show that LDLR-deficient Tg2576 mice developed hypercholesterolemia and age-dependent cerebral beta-amyloidosis. Before the manifestation of amyloid-beta (Abeta) deposition, these mice displayed hyperactivity, reduced anxiety, and impaired spatial learning regardless of LDLR genotypes. After the manifestation of Abeta deposition, LDLR-deficient Tg2576 mice showed more spatial learning deficits than LDLR-intact Tg2576 mice. Although LDLR genotypes did not affect the expression level of the amyloid-beta precursor protein transgene, there was a significant increase in Abeta deposition accompanied with an increase of apoE expression in LDLR-deficient Tg2576 mice. Our results suggest that the LDLR plays a role in the development of Alzheimer-type learning impairment and amyloidosis and can be a novel therapeutic target for AD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Alzheimer Disease / psychology*
  • Amyloid beta-Peptides / metabolism
  • Amyloidosis / pathology*
  • Animals
  • Cholesterol / blood
  • Disease Models, Animal
  • Female
  • Hypercholesterolemia / pathology
  • Male
  • Maze Learning
  • Memory
  • Mice
  • Mice, Transgenic
  • Receptors, LDL / blood
  • Receptors, LDL / deficiency*

Substances

  • Amyloid beta-Peptides
  • Receptors, LDL
  • Cholesterol