Session 7: Membrane pathophysiology and disease
What is the role of lipid domains in Alzheimer's disease?
Jesus Benavides and Patrick Benoit
Alzheimer's disease is the major cause of dementia in the elderly, and its increasing incidence is a major concern for public health in industrialized countries. It is a neurodegenerative disorder characterized by progressive neuronal loss and the accumulation of neurofibrillary tangles and neuritic plaques in brain regions implicated in learning and memory. The neuritic plaques are caused by the accumulation of the toxic amyloid-β peptide (Aβ), which is generated from its membrane-bound precursor, the β-amyloid precursor protein (APP), by the action of two membrane-associated protease activities; β- and γ-secretase.
The co-trafficking of APP and β- or γ-secretase is considered to be a potential mechanism for the modulation of Aβ production, and the presence of β- and γ-secretase in membrane rafts is now widely accepted, as is the accumulation of Aβ in these domains. Furthermore, increasing evidence has been produced during recent years for the modulation of these protease activities through changes in the composition of membrane lipids; particularly cholesterol.
A role for cholesterol in Alzheimer's disease is also suggested by the discovery more than 10 years ago of the strong association of the apolipoprotein E ∈4 allele with late-onset Alzheimer's disease. Polymorphisms in the genes encoding other proteins involved in cholesterol homeostasis, such as cholesterol 24-hydroxylase (CYP46) and ABC transporters, are also associated with an increased risk of developing the disease. More controversial are data associating previous statin treatment with a decreased risk of developing the disease.
Taken together, these observations strongly support the notion that alterations in cholesterol homeostasis play a role in Alzheimer's disease, although a major question is whether this is a direct consequence of changes in cholesterol levels in membrane rafts, or rather reflects indirect effects of changes in cholesterol homeostasis on APP trafficking and Aβ production and clearance. Understanding these mechanisms could open the way to innovative therapeutic approaches.
Further reading
Forman, M. S., Trojanowski, J. Q. & Lee, V. M-Y. Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nature Med. 10, 1055-1063 (2004)
Mattson, M. P. Pathways towards and away from Alzheimer's disease. Nature 430, 631-639 (2004)
Puglielli, L. Tanzi, R. E. & Kovacs, D. M. Alzheimer's disease: the cholesterol connection. Nature Neurosci. 6, 345-351 (2003)
| |
| |
Full list of key questions