Biology Reference
In-Depth Information
The underlying cellular mechanism of Aβ oligomer-induced synaptic modifications has
been examined using a recently described stable oligomeric Aβ preparation called “Aβ 1-42
globulomer”, which localizes to hippocampal neurons and impairs LTP [Barghorn et al.,
2005]. The pathological relevance of Aβ 1-42 globulomer is supported by the observation that
specific antibodies detect globulomer epitopes in brains of AD patients and Aβ-
overproducing transgenic mice [Barghorn et al., 2005]. In a subsequent studt, Aβ 1-42
globulomer was reported to suppress spontaneous synaptic activity by inhibition of P/Q-type
calcium currents [Nimmrich et al., 2008]. Because intact P/Q calcium currents are needed for
synaptic plasticity, the disruption of such currents by Aβ 1-42 globulomer may cause deficits in
cellular mechanisms of information storage in brains of AD patients. These data, however, do
not unambiguously prove that Aβ 1-42 globulomer directly interacts with P/Q-channel subunits.
It is also possible that binding occurs at other synaptic proteins, which then causes a
modification of the P/Q current, perhaps by interacting with the auxiliary subunits of the
channel [Nimmrich et al., 2008].
A novel transgenic mouse model has recently been described, expressing a human APP
with the Swedish and Arctic mutations (arcAβ mice) that produces a form of Aβ more prone
to yield Aβ oligomers [Knobloch et al., 2007a]. In these mice, expression of the mutant APP
induces severe behavioral deficits before the onset of extracellular Aβ plaque formation.
Overexpression of Arctic Aβ is associated with an age-dependent impairment in hippocampal
LTP and synaptic plasticity in vitro that involves protein phosphatase 1-dependent
mechanisms [Knobloch et al., 2007b]. Futhermore, the pharmacologic and genetic inhibition
of protein phosphatase 1 in vitro and in vivo reversed the defect in synaptic plasticity induced
by Aβ oligomers. These findings support a role for protein phosphatase 1 in the mechanisms
of Aβ oligomer-mediated synaptotoxicity.
Glucose tolerance and insulin
Poor glucose tolerance and memory deficits, short of dementia, often accompany aging.
Indeed, there is a growing literature indicating that individuals with diabetes have
impairments in recent memory [Richardson, 1990; Stewart and Liolitsa, 1999; Biessels et al.,
2001; Strachan et al., 2000]. In addition, nondiabetic individuals with mild forms of impaired
glucose tolerance (IGT) may also have cognitive impairments [Vanhanen et al., 1997; Kaplan
et al., 2000]. The prevalence of memory problems and IGT rise with age [Harris et al., 1987;
Shimokata et al., 1991; Unverzagt et al., 2001]. In addition to genetic predisposition, obesity
and low levels of physical activity have been identified as risk factors for IGT in adults and
children [Fagot-Campagna, 2000; Astrup, 2001]. With life expectancy and obesity on the rise,
the prevalence of memory dysfunction and IGT will likely continue to climb. Hypothalamus-
pituitary-adrenal axis hyperactivity has been associated with hippocampal atrophy in aging
[Lupien et al., 1998]. Cortisol administration reduces glucose transport into neurons [Horner
et al., 1990] and causes reductions in hippocampal glucose utilization [de Leon et al., 1997],
which may explain why animals that have abnormal glucose metabolism have more
hippocampal damage when exposed to high levels of corticosteroids [Magariños and
McEwen, 2000]. In addition to the higher prevalence of memory problems and IGT
mentioned above, age-associated reductions in hippocampal volumes have also been reported
[Convit et al., 1995]. Moreover, a recent study has shown that among nondiabetic,
nondemented middle-aged and elderly individuals, decreased peripheral glucose regulation
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