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