Jonny Daborg
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small dendritic protrusions called spines, and the Lai et al. (2012) study
suggests that elimination of synapses are directly involved in learning;
alternatively that impaired elimination leads to an inefficient neuronal
network, or perhaps most likely, both. Either way, the study strongly
implicates the process of synaptic elimination in the formation of memories.
The details of the elimination process are largely unknown, but it has been
shown that the complement system is somehow involved (Stevens et al.
2007; Paolicelli et al. 2011; Chu et al. 2010; Schafer et al. 2012).
The complement system is probably better known for its role in the innate
immune response. It consists of more than thirty proteins, mainly zymogens,
which when activated, aggregate and catalyse the formation of active
complement components, forming a cascade that ultimately works to
eliminate foreign objects such as pathogens (Sarma and Ward 2011). This is
done either by opsonisation and attraction of macrophages, or by formation
of the membrane attack complex which forms a pore in the infected cell
membrane and thereby induces direct cell lysis. Exactly how complement
proteins work to eliminate synapses is still not known. However, elimination
is most likely initiated by complement component 1q (C1q) (Stevens et al.
2007), the starting point of the classical complement cascade.
Studies of transgenic mice, lacking the genes encoding C1q and complement
component 3 (C3) revealed that the complement system is involved in
eliminating retinogeniculate connections (Stevens et al. 2007) and synapses
in the sensorimotor cortex (Chu et al. 2010). A role for microglia has been
implicated by showing how inhibition of microglial motility resulted in
defective synapse elimination in the hippocampus (Paolicelli et al. 2011). In
addition, Paolicelli and colleagues (2011) also reported that they found the
postsynaptic density protein PSD95 in microglia, suggesting that these cells
engulf synapses. A recent study corroborates this by presenting evidence for
that retinogeniculate synapses are actually engulfed by microglia, at least the
presynaptic portion (Schafer et al. 2012). It was further shown that this was
dependent on the complement component 3 receptor (C3R) and C3 signalling
(Schafer et al. 2012).
Aside from the complement system the proteins semaphorin 3A/F and 5B,
and ephrin have also been implicated in synapse elimination (Bagri et al.
2003; O'Connor et al. 2009; Tada and Sheng 2006; Fu et al. 2007). Another
group of proteins that have been implicated are the neuronal pentraxins
(Bjartmar et al. 2006). This is interesting since some of these molecules are
situated in synapses (Gerrow and El-Husseini 2007) and can bind C1q
Synaptic elimination and the complement system in Alzheimer’s disease
14
(Sarma and Ward 2011), thus providing a potential platform for the classical
complement cascade.
1.3
Synaptic pathophysiology in AD
The major clinical hallmark of AD is amnesia, and as already mentioned, Aβ
seems to play a central role in AD pathogenesis. Interestingly, the pathology
usually debuts in the hippocampal formation in the temporal lobe of the
brain; an anatomic structure that is intimately associated with learning and
memory (Squire and Wixted 2011). Since the cellular substrate for learning
and memory is thought to be LTP, Aβ might in some way inhibit LTP.
Indeed, quite a few animal studies have shown this for a fact (Shankar et al.
2008; Townsend et al. 2007; Walsh et al. 2002; Klyubin et al. 2008;
Knobloch et al. 2007; Kamenetz et al. 2003; Chang et al. 2006; Chapman et
al. 1999). The mechanism by which Aβ inhibits LTP is not clear however,
but a number of pathways have been implicated through various experimental
studies. The phosphatases: calcineurin (Chen et al. 2002), PP1 (Knobloch et
al. 2007), and striatal enriched phosphatase (Chin et al. 2004); the kinases:
p38 MAPK (Wang et al. 2004), cdk5 (Wang et al. 2004), Erk/MAPK
(Townsend et al. 2007), Akt/PKB (Townsend et al. 2007), GSK3β (Koh et al.
2008; Takashima et al. 1996), PKA/CREB (Vitolo et al. 2002), and CAMKII
(Townsend et al. 2007; Zhao et al. 2004); the insulin receptor (Townsend et
al. 2007), the receptor for advanced glycation end products (RAGE) (Arancio
et al. 2004; Origlia et al. 2009; Origlia et al. 2008), glutamate uptake (Li et al.
2009) and the prion protein (Kessels et al. 2010; Barry et al. 2011) have all
been shown to be implicated in the Aβ-induced LTP inhibition.
There are also some studies suggesting that the threshold for LTD is lower in
animal models of AD (Hsieh et al. 2006; Li et al. 2009; Cheng et al. 2009).
This is very interesting since it has also been shown that LTD can lead to
synapse elimination (Nagerl et al. 2004; Shinoda et al. 2005; Kamikubo et al.
2006; Bastrikova et al. 2008; Becker et al. 2008) and loss of synapses is the
pathophysiological feature of AD brains that best correlates with the severity
of the symptoms (Scheff and Price 2003; DeKosky and Scheff 1990; Terry et
al. 1991).
Other studies have shown that application of Aβ to a slice of hippocampal
tissue induces synapse elimination in the slice (Qu et al. 2011; Shankar et al.
2007; Shrestha et al. 2006). Knockout mice, lacking APP have been shown to
have more synapses than wild type (WT) mice (Priller et al. 2006);
conversely, transgenic mice overexpressing human APP have fewer synapses
than WT mice (Koffie et al. 2009; Smith et al. 2009; Qu et al. 2011).