Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model.

By L. Refolo, M. Pappolla, B. Malester, J. Lafrancois, T. Bryant‐Thomas, Rong Wang, G. Tint, K. Sambamurti, K. Duff. Neurobiology of Disease, 2000

1,021 citations recorded by the source corpus.

Recent data suggest that cholesterol metabolism is linked to susceptibility to Alzheimer's disease (AD). However, no direct evidence has been reported linking cholesterol metabolism and the pathogenesis of AD. To test the hypothesis that amyloid beta-peptide (Abeta) deposition can be modulated by diet-induced hypercholesterolemia, we used a transgenic-mouse model for AD amyloidosis and examined the effects of a high-fat/high-cholesterol diet on central nervous system (CNS) Abeta accumulation. Our data showed that diet-induced hypercholesterolemia resulted in significantly increased levels of formic acid-extractable Abeta peptides in the CNS. Furthermore, the levels of total Abeta were strongly correlated with the levels of both plasma and CNS total cholesterol. Biochemical analysis revealed that, compared with control, the hypercholesterolemic mice had significantly decreased levels of sAPPalpha and increased levels of C-terminal fragments (beta-CTFs), suggesting alterations in amyloid precursor protein processing in response to hypercholesterolemia. Neuropathological analysis indicated that the hypercholesterolemic diet significantly increased beta-amyloid load by increasing both deposit number and size. These data demonstrate that high dietary cholesterol increases Abeta accumulation and accelerates the AD-related pathology observed in this animal model. Thus, we propose that diet can be used to modulate the risk of developing AD.

Subfields: Molecular Biology, Physiology, Surgery

View Paper: https://www.semanticscholar.org/paper/318a12013c01fd8b92a5ea28dd3f43e4ab03dcd0

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In Molecular Biology

1. K. Simons
2. D. Selkoe
3. R. Ehehalt
4. M. Sheng
5. John Hardy
6. Christian Haass
7. David Watson
8. G. Nicolson

In Physiology

1. Christian Haass
2. K. Simons
3. D. Selkoe
4. John Hardy
5. R. Ehehalt
6. D. Holtzman
7. G. Bu
8. David Watson

Citations in the corpus

• Oleuropein in Olive and its Pharmacological Effects (2010, background): “The link between heart disease, hypercholesterolemia, and AD [83] is due to similar mechanisms of pathogenesis of these disorders.”
• Human Health Risk Assessment for Aluminium, Aluminium Oxide, and Aluminium Hydroxide (2007, background): “Recent studies from a number of laboratories ( Refolo et al, 2000 ; Smith et al, 2001 ) demonstrated that the proteolytic generation of amyloid peptide (the principal component of senile plaques in AD patients) is elevated by hypercholesterolemia.”
• Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts (2003, background): “…Biology | Volume 160, Number 1, 2003 etary cholesterol uptake increased amyloid plaque formation in rabbits and transgenic mice (Sparks et al., 1994; Refolo et al., 2000), and cholesterol loading and depletion affected A generation in cultured cells and in an animal model (Simons et al., 1998;…”
• Lipid Rafts in the Maintenance of Synapses, Dendritic Spines, and Surface AMPA Receptor Stability (2003, background): “Moreover, the cleavage of amyloidprecursor protein to A is modulated by levels of membrane cholesterol (Simons et al., 1998; Refolo et al., 2000).”
• The amyloid hypothesis of Alzheimer's disease at 25 years (2016, background): “…and other components of cholesterol/sterol metabolism A role for cholesterol in AD has long been suspected, based on the genetic implication of ApoE in the disease as well as the contrasting effects of cholesterol loading or depletion on amyloid pathology in APP tg mice (Refolo et al, 2000, 2001).”