Grace Stutzmann Rosalind Franklin University/The Chicago Medical School
Posted:
This is an exciting, concise study demonstrating that wild-type presenilin (PS) is required for a critical aspect of synaptic homeostasis, namely, synaptic scaling, which reflects a neuron’s ability to dynamically alter its responses in an activity-dependent manner. Pratt et al. describe how the absence of PS, or the expression of FAD-linked mutant PS, impairs the ability of neurons to "recalibrate" to changes in network activity. Notably, the spontaneous synaptic potentials in the PS-manipulated neurons appear inherently normal, but they lack the ability to respond to changing stimuli, likely due to impaired downstream PI3K/Akt signaling. These findings are inherently interesting in that they link mutations known to cause AD with a mechanism of impaired synaptic scaling, thereby supporting an increasingly investigated hypothesis that there are subtle, underlying deficits in synaptic function occurring long before overt symptoms of AD pathology.
On a broader perspective, these findings also integrate into a larger arena regarding early, "below the radar" deficits in neuronal functioning linked to AD pathology. Much research is focused on the salient, late-stage features (e.g., amyloid aggregates, tangle formation, and cell death), but these likely represent the "end of the line" of the pathogenic cascade. Studies such as these demonstrate that there are subtly destructive mechanisms operating much earlier in the disease process that alter the synaptic circuitry and metaplasticity that support learning, memory, and higher cognitive functions. A critical mass of synapses that lack the ability to adapt to changing activity levels can threaten the whole circuit, not unlike a few rusty wires short-circuiting the whole machine. Although targeting the late-stage markers of AD may be a desirable therapeutic goal, it seems, in light of the present study by Pratt et al., as well as complementary studies (Müller et al., 2011; Goussakov et al., 2010), that identifying earlier, substantive changes in neuronal function may provide mechanisms to actually alter the course of cognitive loss in AD.
References:
Müller M, Cárdenas C, Mei L, Cheung KH, Foskett JK.
Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling.
Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13293-8.
PubMed.
Goussakov I, Miller MB, Stutzmann GE.
NMDA-mediated Ca(2+) influx drives aberrant ryanodine receptor activation in dendrites of young Alzheimer's disease mice.
J Neurosci. 2010 Sep 8;30(36):12128-37.
PubMed.
Comments
Rosalind Franklin University/The Chicago Medical School
This is an exciting, concise study demonstrating that wild-type presenilin (PS) is required for a critical aspect of synaptic homeostasis, namely, synaptic scaling, which reflects a neuron’s ability to dynamically alter its responses in an activity-dependent manner. Pratt et al. describe how the absence of PS, or the expression of FAD-linked mutant PS, impairs the ability of neurons to "recalibrate" to changes in network activity. Notably, the spontaneous synaptic potentials in the PS-manipulated neurons appear inherently normal, but they lack the ability to respond to changing stimuli, likely due to impaired downstream PI3K/Akt signaling. These findings are inherently interesting in that they link mutations known to cause AD with a mechanism of impaired synaptic scaling, thereby supporting an increasingly investigated hypothesis that there are subtle, underlying deficits in synaptic function occurring long before overt symptoms of AD pathology.
On a broader perspective, these findings also integrate into a larger arena regarding early, "below the radar" deficits in neuronal functioning linked to AD pathology. Much research is focused on the salient, late-stage features (e.g., amyloid aggregates, tangle formation, and cell death), but these likely represent the "end of the line" of the pathogenic cascade. Studies such as these demonstrate that there are subtly destructive mechanisms operating much earlier in the disease process that alter the synaptic circuitry and metaplasticity that support learning, memory, and higher cognitive functions. A critical mass of synapses that lack the ability to adapt to changing activity levels can threaten the whole circuit, not unlike a few rusty wires short-circuiting the whole machine. Although targeting the late-stage markers of AD may be a desirable therapeutic goal, it seems, in light of the present study by Pratt et al., as well as complementary studies (Müller et al., 2011; Goussakov et al., 2010), that identifying earlier, substantive changes in neuronal function may provide mechanisms to actually alter the course of cognitive loss in AD.
References:
Müller M, Cárdenas C, Mei L, Cheung KH, Foskett JK. Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling. Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13293-8. PubMed.
Goussakov I, Miller MB, Stutzmann GE. NMDA-mediated Ca(2+) influx drives aberrant ryanodine receptor activation in dendrites of young Alzheimer's disease mice. J Neurosci. 2010 Sep 8;30(36):12128-37. PubMed.
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