Lipid metabolism and Alzheimer’s disease

Makoto Michikawa

Department of Biochemistry, Nagoya City University, Graduate School of Medical Sciences

Alzheimer’s disease is characterized by the progressive accumulation of extracellular deposits of the amyloid β-peptide (Aβ) and intraneuronal aggregates of the microtubule associated protein tau. Genetic, biochemical, and biological evidence suggest that Aβ plays critical roles in the initiation of the pathogenic process. Aβ is generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretases. Whareas, APP is also cleaved by α-secretase within the Aβ domain, thereby precluding subsequent production of Aβ. Because these three secretases and APP are membrane proteins, which are subjected to the secretory and endocytic trafficking pathways, the membrane lipid composition could play important roles in modulating trafficking and metabolism of these proteins. The fact that membrane lipids such as cholesterol and sphingolipids are abundant and characteristic components of neuronal membranes, has led us to focus on the roles of these lipids and metabolites in the pathogenesis of AD. Another point to be stressed is that lipid metabolism in the brain is segregated from that of systemic circulation by blood-brain-barrier and thus these two system should be discussed independently. In this review, numerous papers are classified due to these two viewpoints and discussed the possible roles of lipids in pathomechanism(s) underling AD.

Address correspondence to Dr. Makoto Michikawa, Department of Biochemistry, Nagoya City University, Graduate School of Medical Sciences (Kawasumi 1, Mizuho, Nagoya, Japan)