Biology Reference
In-Depth Information
Type II diabetes is associated with high synthesis and low absorption of cholesterol, and
insulin-resistant patients have increased cholesterol synthesis [Pihlajamäki
et al.,
2004].
Several lines of evidence have implicated a role for cholesterol in AD: elevated cholesterol is
associated with increased risk for AD [Evans
et al.,
2004]; AD patients have elevated levels
of total serum cholesterol and LDL (low density lipoprotein)-associated cholesterol [Jarvik
et
al.,
1995]; the ε4 mutant in the gene for ApoE (apolipoprotein E), and important cholesterol
transport protein associated with LDL, is a risk factor for AD [Breitner
et al.,
1999].
Cholesterol may not only promote AD indirectly by promoting cardiovascular disease, but
also more directly by interacting with APP. Cholesterol binds to APP and Aβ near the α-
secretase cleavage site, and Aβ
1-42
competitively inhibits cholesterol binding to ApoE and
LDL [Yao and Papadopoulos, 2002].
ApoE is a component of several classes of lipoproteins regulating lipid metabolism and
distribution [Mahley and Huang, 1999]. ApoE isotype ε4 is a risk factor for familial and late-
onset (>65 years) sporadic AD (LOAD) [Breitner
et al.,
1999], and early-onset familial AD
(FAD) (<65 years) [Roses
et al.,
1995; Meyer, 1998]. The major epidemiological effect of ε4
in AD is to promote an earlier age of onset that ε3, typically by about 5 years but as much as
15 years [Meyer, 1998; Mesulam, 1999; Ashford and Mortimer, 2002]. Because AD is
characterized by ongoing neurodegeneration, accelerated clinical onset could be caused by
defects in ApoE-related compensatory mechanisms that repair circuitry [Mesulam, 1999;
Teter, 2000]. Differential intracellular trafficking may underlie ApoE isotype effects on
plasticity. ApoE isotypes localize differentially and accumulate in neurons and astrocytes [Xu
et al.,
1998]. AopE isotypes may be sorted into late endosomes, escaping lysosomal
hydrolysis, where they can differentially mediate intracellular processes [Mahley and Rall,
2000]. Several lines of transgenic mice have been developed that express the human AopE
isotypes under the transcriptional control of various promoters [reviewed in Teter and
Ashford, 2002]. In one such line, only female ε4 transgenic mice (under control of the
neuron-specific NSE promoter) develop age-related progressive impairments in spatial
learning and memory [Raber
et al.,
1998], a finding consistent with the epidemiological
interaction of Apoε4 and female gender on increased risk to develop AD.
Recently, the neuronal sortilin-related receptor SorLA/LR11 (LR11), a member of the
ApoE/LDL receptor family, was identified as a probable risk factor for LOAD [Rogaeva
et
al.,
2007]. LR11 functions as a sorting and trafficking protein, guiding APP into the recycling
endosome pathways that lead to a reduction of Aβ production [Offe
et al.
, 2006].
Polymorphisms associated with increased AD risk appeared to reduce LR11 mRNA in ~15%
of AD cases. Furthermore, neuronal LR11 expression is reduced in the overall LOAD
population but not in familial AD pathology [Dodson
et al.,
2006]. This argues that LR11
deficits in LOAD are not simply secondary to pathology and might play a causal role.
Because lipoprotein receptor family proteins are frequently lipid-regulated, for example by
cholesterol or essential fatty acids [Zheng
et al.,
2002], dietary lipids might be expected to
increase LR11 expression and thereby reduce AD risk. The only plasma lipid predictive of
AD risk in the Framingham study was docosahexaenoic acid (DHA), an essential ω-3 fatty
acid related to reduced AD risk and reduced Aβ accumulation [Johnson and Schaefer, 2006].
Dietary DHA significantly improved cognitive deficits, protected synaptic protein loss and
lowered insoluble Aβ in an aged DHA-depleted transgenic AD mouse model (Tg2576),
apparently by reducing Aβ production [Calon
et al.,
2004; Lim
et al.,
2005]. DHA mediated
