Biology Reference
In-Depth Information
context, a recent study describes neural stem cell transplantation into the hippocampus of a
transgenic model with targeted neuronal cell loss and consequent improvement in short-term
memory on a spatial task in a time-dependent manner [Yamasaki
et al.,
2007]. The fact that
the stem cells localized to the hippocampus in induced mice is consistent with the selective
improvement seen on the hippocamal-dependent task, but not on the corically dependent task
[Yamasaki
et al.,
2007]. Trophic mechanisms are likely to contribute to the improvement of
memory in the last model. Increases in BDNF occur after brain injury [Kokaia
et al.,
1998]
and BDNF has also been shown to upregulate synapsin [Causing
et al.,
1997]. The levels of
synapsin seen in induced neural stem cell transplanted mice were significantly greater than
those seen in lesioned vehicle-injected controls at the CA1 region of the hippocampus
[Yamasaki
et al.,
2007], and are consistent with neurotrophin-induced sprouting.
Neurotrophins may contribute also to the neuronal sparing effect seen at both the dentate
gyrus and CA1 region of neural stem cell transplanted mice resulting in memory
improvement. Although these authors did not see an increase in endogenous neurogenesis
with lesioning, neurotrophin-mediated augmentation of endogenous neurogenesis has been
described by others [Zigova
et al.,
1998; Yoshimura
et al.,
2001].
Inflammation and synaptic plasticity
Recent evidence suggests an inflammatory component in AD, which is characterized by
astrogliosis, microgliosis, cytokine elevation, and changes in acute phase proteins [Wyss-
Coray, 2006]. Tumor necrosis factor-α (TNF-α) is a cytokine thought to play a central role in
the self-propagation of neuroinflammation [Perry
et al.,
2001]. Increased levels of TNF-α in
the brain and plasma of AD patients and an upregulation of TNF receptor 1 have been
detected in the AD brain [Fillit
et al.,
1991; Li
et al.,
2004]. As already discussed, synaptic
dysfunction has gained increasing recognition as an important pathophysiological component
of AD. TNF-α may well be involved in such dysfunction. In experimental models, TNF-α
alters synaptic transmission in rat hippocampal slices [Tancredi
et al.,
1992], and TNF-α
released by glia controls synaptic strength [Beattie
et al.,
2002; Stellwagen
et al.,
2006]. This
cytokine may also act as a mediator of Aβ oligomer disruption of memory processes [Wang
et al.,
2005]. The underlying mechanism is not known, but may involve synaptic scaling. The
latter has been suggested to be a key component in the synaptic dysfunction of AD [Small,
2004]. Synaptic scaling involves uniform adjustments in the strength of all synaptic
connections for a neuron in response to changes in the neuron's electrical activity [Turrigiano
and Nelson, 2004; Stellwagen and Malenka, 2006], and is a homeostatic mechanism which
serves for the optimal functioning of neural networks. As synaptic scaling can be regulated by
TNF-α [Stellwagen and Malenka, 2006], synaptic dysregulation produced by excess TNF-α
[Fillit
et al.,
1991; Ramos
et al.,
2006; Álvarez
et al.,
2007; Tan
et al.,
2007] may contribute
to cognitive and behavioral deficits in AD. Preliminary clinical studies investigating
anatomically targeted anti-TNF-α treatment have been reported with encouraging [Tobinick
et al.,
2006; Tobinick and Gross, 2008], albeit cautionary outcome. Intriguingly, a
concentration-dependent duality effect has also been observed for interleukin-1, with the
cytokine regulating hippocampal slice LTP under physiological conditions but inhibiting at
higher doses [Ross
et al.,
2003].
