Institutionen för neurobiologi, vårdvetenskap och samhälle / Department of Neurobiology, Care Sciences and Society
Abstract
BACKGROUND: Alzheimer s disease (AD) is a severe neurodegenerative
disease that mainly afflicts elderly persons, with a characteristic
progressive decline of cognitive functions and dementia. It is believed
that the majority of all AD patients are affected by the sporadic form,
thus caused by the combined effects of several risk factors, such as
elevated cholesterol levels in midlife and deficiencies in the
lipoprotein transporters apolipoprotein E (ApoE). Cholesterol play an
essential role in the central nervous system (CNS) were it maintains
normal physiological conditions, and is a requirement for the ability of
neurons to communicate. It has previously been demonstrated that the
cholesterol homeostasis in the CNS is maintained by a slow conversion of
brain cholesterol into 24(S)-hydroxycholesterol, with a net flux of
27-hydroxycholesterol from the circulation into the brain. The importance
of a preserved cholesterol homeostasis has been supported by the
observation that dietary cholesterol may induce an inflammation in the
CNS, and increase the levels of pro-inflammatory mediators. It has, in
direct association with these observations, been demonstrated that plasma
levels of pro-inflammatory proteins, such as interleukin-6, are increased
before the clinical onset of AD, after which a chronic state of
inflammation often is found. Accordingly, it has been suggested that
memory and cognitive functions could benefit from a cholesterol-lowering
therapy. STUDIES: The research presented in this thesis has examined the
effect of cholesterol and cholesterol-lowering therapy with rosuvastatin,
on key factors associated with AD. The experimental setup consisted of in
vitro-models with human neuroblastoma SH-SY5Y cells (paper I II), and in
vivo-models with wild type (WT) and ApoE knockout (ApoE-/-) mice,
provided with high levels of dietary cholesterol for 18 weeks (paper
III IV). The hydrophilic compound rosuvastatin is an effective inhibitor
of cholesterol synthesis and has been demonstrated to be an effective
treatment for hypercholesterolemia, with an indirect effect on microglial
activation and inflammation through isoprenoid depletion. RESULTS: Paper
I describes the selective non-amyloidogenic processing (alpha-secretase
activity) of the amyloid precursor protein (APP), induced by
24(S)-hydroxycholesterol, with a subsequent increased ratio of
alpha-/beta-secretase activity, and increased levels of soluble APPalpha
and total soluble sAPP; effects significantly decreased by the presence
of 27-hydroxycholesterol. Paper II describes the effect of pre-treating
in vitro-cultures with rosuvastatin prior exposure to Abeta oligomers.
The treatment was found to decrease caspase-3 activity and promote cell
survival, with a selective non-amyloidogenic processing of APP. However,
no influence was observed on cell viability, with a potential explanation
in a downregulated metabolism. Paper III IV describes the effect of high
levels of dietary cholesterol in vivo, with increased microglial
activation in WT mice, increased gliosis in ApoE-/- mice and subsequent
increased plasma IL-6 levels in WT and ApoE-/- mice. The elevated levels
of total cholesterol (TC) were found to be caused by increased levels of
HDL and LDL in WT mice, whereas only LDL where increased in ApoE-/- mice.
Plasma TC levels were correlated with body weight gain in WT and ApoE-/-
mice. Furthermore, the selective and ApoE-associated influence induced by
the rosuvastatin therapy, on the effects of dietary cholesterol, is
described. We observed a decreased microglial activation and gliosis in
WT and ApoE-/- mice, with plasma IL-6 levels decreased by 45% in WT mice,
without reaching significance. The elevated levels of TC and LDL were
decreased in WT mice, whereas no effect was observed on the levels of TC,
HDL or LDL in ApoE-/- mice. Body weight gain was decreased in WT mice,
with a previously unpublished age- and ApoE-associated declining response
to the therapy observed in ApoE-/- mice. SUMMARY: The presented thesis
has examined the connection between Alzheimer s disease and cholesterol,
and demonstrated a selection of detrimental effects which may be induced
by high levels of dietary cholesterol. Furthermore, the thesis has
demonstrated the potential for a cholesterol-lowering therapy with
rosuvastatin to exercise a preventive influence, with an age- and
ApoE-associated response. The latter is an important observation, which
indicates that rosuvastatin may be an effective therapy up to a certain
point in the progression of the disease, after which the effects decline.
In conclusion, the results discussed in this thesis offer a hypothetical
explanation, at least in part, for the discrepancies observed in clinical
trials on statins. In addition, this thesis have been able to support the
theoretical connection between AD and plasma cholesterol levels with the
observation that 27-hydroxycholesterol may exhibit an inhibitory
influence on 24(S)-hydroxycholesterol and non-AD processes. It is
suggested that persons with high risk of developing AD may benefit from a
rosuvastatin therapy, in combination with lifestyle precautions taken in
early midlife. The approach could be an effective lifestyle-preventive
strategy, with preserved cognitive functions and quality of life at high
age