Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study

To update readers
on the hot subject of cholesterol and Alzheimer's pathogenesis (
BMJ 2001;
322:
1447-51 and BMJ
2001; 323: 771 ) we would like to notice that today the role
of cholesterol in AD is mainly discussed in the context of the reduction
of  amyloid burden by lowering cholesterol (for reviews see Ref.
1). This viewpoint is based on more then dozen reports implicating
cholesterol in amyloid precursor protein processing and amyloid b
protein (Ab) generation in cell cultures and
in laboratory animals.

The paper by Yamazaki et al. [ 2 ] and very
recent contribution by Puglielli et al. [ 3
] further reported that cellular generation of Ab
is modulated by cholesterol compartmentation and intracellular cholesteryl-ester
levels.

We would like to add important missing discussion venue.

We and others reported previously that near physiological concentrations
of Ab inhibit cholesterol esterification [ 4,5 ]. Ab also increases lipid
synthesis (specifically that of cholesterol and phospholipids) in PC12
and rat primary neuronal cell cultures, fetal brain, and in ex vivo hippocampal
slices; cellular cholesterol uptake (see Ref. 6 for
detailed bibliography); and lipid efflux [ 7 ]; and
modulates membrane physical properties [ 8,9
].

Taken together, the data by Puglielli et al. and our data indicate feedback
functional relation between Acyl-coenzyme A:cholesterol acyltransferase-catalyzed
cholesterol esterification, cholesterol esterase-catalyzed cholesteryl-ester
hydrolysis [ 10 ],  and Ab.
In this light additional facilitation of neuronal cholesterol synthesis,
cholesterol cellular uptake and cholesterol efflux by Ab
[ 6,7 ] may contribute to the
efficiency with which neurons coordinate the influx, efflux, synthesis,
and esterification of free cholesterol, and the release of cholesterol
from the ester storage pool [ 10 ].

However, the failure in the dynamic equilibrium of the complex processes
of tight regulation of intracellular cholesterol is important not only
for the excessive Ab generation [ 3
], but also for synaptic functional failure and excessive tau phosphorylation,
another Alzheimer’s hallmarks. Thus, neuronal cholesterol homeostasis decay
(experimentally achieved by cholesterol synthesis inhibition or increased
cholesterol efflux) causes paired helical filaments (PHF)-tau phosphorylation
and is sufficient to induce neurotransmission and synaptic plasticity impairment
in rat hippocampus [ 6,11 ].
As it was proposed [ 12 ] and discussed [ 6
], the change in both Ab
and tau protein neurochemistry may independently help to recover synaptic
function and plasticity, the neurodegeneration aim, that in AD may well
be caused by neuronal cholesterol turnover misregulation[ 6,13 ], a welcome question
indeed.