Loss of activated CaMKII at the synapse underlies Alzheimer’s disease memory loss

The main symptom of Alzheimer’s disease (AD) patients is memory loss. At the microscopic level, early symptoms of memory perturbation likely involves the loss of synapses, which is one of the strong correlates of cognitive integrity. Many studies also have demonstrated that memory loss originates from synaptic failure, which precedes neuronal death. However, the mechanism by which synaptic integrity becomes compromised has not been clearly defined. In this recent article, Reese and colleagues demonstrated that the dysregulation of the calcium-camodulin kinase IIα (CaMKII) activity at the dendritic arbor could underlie the pathology of memory loss seen in AD patients (Reese et al. 2011). Under physiological condition, the number of NMDA-type glutmate receptor is tightly associated with synaptic transmission. Moreover, NMDA receptors can either induce long-term potentiation (LTP) or long-term depression (LTD), depending on the extent of intracellular calcium rise in the dendritic spines and the activation of downstream signal transduction cascades (Kullmann and Lamsa 2007). The state of protein phosphorylation is highly important in regulating the integrity of the post-synaptic density. For example, protein phosphorylation of various glutamate receptors will facilitate trafficking and insertion into the synaptic site. Moreover, protein phosphorylation of docking proteins by protein kinases at the synapse will enhance protein–protein binding and formation of new spines. Conversely, protein dephosphorylation by phosphatase at the synapse could be involved in receptor desensitization and internalization. The extent of intracellular rise in calcium levels appears to be the most upstream regulator of protein phosphorylation/dephosphorylation events at the synapse. The induction of LTP requires a higher intracellular calcium rise and activation of a whole series of protein phosphorylation events that lead to synapse stabilization and recruitment of more glutamate receptor to the synaptic site. However, lower intracellular calcium and induction of protein phosphatases lead to glutamate receptor internalization is required for LTD. LTP promotes formation of more dendritic spines associated with learning and memory. In contrast, LTD induces spine shrinkage and synaptic loss. Deposition of amyloid β proteins (Aβ) to form neuritic plaque is the hallmark of AD neuropathology. According to the amyloid hypothesis, AD is caused by the abnormal accumulation and aggregation of neurotoxic Aβ in the brain. The current emerging concept hypothesizes that it is the soluble oligomeric form of Aβ causing impaired synaptic transmission and cognitive functions, and accumulation of Aβ triggers a complex cascade of molecular and cellular changes that translates to clinical signs observed in AD patients. Therefore, a thorough understanding of how Aβ accumulates and how it compromises synaptic integrity will provide insights to the development of novel therapeutics for treating AD. Aβ is derived through two sequential cleavages of the β-amyloid precursor protein. First, the β-secretase (BACE1) cleaves β-amyloid precursor protein at the Asp-1 β-site to generate a C99 fragment then followed by γ-secretase cleavage within the transmembrane domain to release Aβ (Li et al. 2006). Naturally Aβ in brain lysates and cerebrospinal fluids are heterogenous in length, but the majority of research studies conducted used the relatively abundant forms of either 40 or 42 amino acids (Selkoe 2008). Moreover, Aβ undergoes a series of oligomerization followed by formation of fibrils. Recent studies showed that the soluble oligomers of Aβ exert a toxic effect to neurons. Both synthetic and naturally derived Aβ treated to cell culture and animal models lead to perturbed intracellular calcium levels and disruption of the activity dependent LTP (Wang et al. 2002; Cleary et al. 2005; Snyder et al. 2005). However, the mechanism underlying these changes remains elusive. CaMKII is one of the main components of the post-synaptic density (PSD) and plays an important role in synaptic transmission. Upon LTP induction, calcium activated camodulin binds CaMKII and triggers a series of autophorylation events. Autophosphorylation at the threonine residue 286 has been associated with enhanced kinase activity and association with the synapse, whereas dephoshorylation at this residue prevented LTP (Giese et al. 1998; Shen and Meyer 1999). In the current study, Reese et al. (2011) demonstrated using quantitative immunofluorescence that the active, phosphorylated form of CaMKII termed p(Thr286)CaMKII was significantly reduced in the hippocampal dendrites of patients with mild cognitive impairment (MCI) and AD. However, they found that the level of p(Thr286)CaMKII was higher in the neural parikarya of these patients examined. The subcellular shift of p(Thr286)CaMKII from dendrites to parikarya correlated with decreased cognitive scores, indicating loss of p(Thr286)CaMKII at the synapse leads to memory dysfunction. The authors speculated that the subcellular profiles of protein phosphatase during AD pathogenesis could explain the synaptic loss of p(Thr286)CaMKII. As the synaptic version of CaMKII is involved in regulating synaptic transmission, this redistribution may indicate that loss of synaptic CaMKII may be a pathological event in AD (Fig. 1). As some of the MCI patients progress to AD, it is very possible that the loss of synaptic CaMKII is one of the initial changes in memory perturbation and could serve as an early indicator of memory loss. The role of oligomeric Aβ and activated CaMKII in AD learning and memory deficits. Calcium signaling in the dendritic spine is an absolute required for synaptic plasticity. Neuronal activity leads high levels of intracellular calcium, which in turn activate CaMKII to further change a series of subcellular events to increase dendritic spine size and number. This results in enhanced learning and memory abilities. Oligomeric Aβ has been found to aberrantly increase calcineurin activity, a protein phosphatase known to dephosphorylate and inactivate CaMKII, leading to suppressed long term potentiation. The dendritic loss of activated CaMKII appears to be an early event in memory perturbation seen in Alzheimer’s disease and could potentially serve as a biomarker for early detection of this disease. As synaptic calcium levels play an important role in regulating a plethora of kinases and phosphatase that facilitate or inhibit long-term potentiation, therapeutic strategies aiming to restore this calcium balance in the synapse could be a new avenue for treating Alzheimer’s disease. Why is the p(Thr286)CaMKII reduced at the PSD? Reduced p(Thr286)CaMKII could not be due to reduced CaMKII trafficking and local synthesis, since the non-phosphoyrlated CaMKII levels in the hippocampi were comparable between MCI, AD, and control subjects. Previous studies have found that both naturally derived and synthetic Aβ disrupts calcium homeostasis, which leads to disruption of LTP and impairment in learning and memory. A modest increase in intracellular calcium levels promotes LTD, which is induced following a protein phosphatase cascade, in part mediated by the phosphatase calcineurin. Activation of calcineurin through a series of steps lead to dephosphorylation of p(Thr286)CaMKII, and has been associated with receptor internalization and subsequent dendritic spine loss (Hudmon et al. 2005). Reese et al. (2011) demonstrated that mice pre-treated with a calcineurin inhibitor prior to Aβ stimulation prevented the dysregulation of p(Thr286)CaMKII in the hippocampus. Reduced CaMKII threonine 286 phosphorylation in the PSD implies that its physiological role at the dendritic arborization will be diminished. The localization of p(Thr286)CaMKII in the PSD has significant functions including promotion of AMPA-type glutamate receptors mediated synaptic activities and maintaining the PSD integrity. Indeed, Reese et al. (2011) reported that reduced p(Thr286)CaMKII in the dendrites correlated with shrinkage of the PSD. Currently, there is no cure for AD and the treatment strategies have only achieved minimal success. This is mainly caused by end-stage diagnosis of AD. An effective treatment strategy will require early diagnosis and preventing synaptic loss prior to memory loss. This new study could provide insights into identification of new biomarkers for early diagnosis and novel targets for AD drug development. The subcellular shift of p(Thr286)CaMKII, could be used as an early diagnostic marker to identify subjects that are at risk of memory loss. New therapeutic strategies could also take into consideration of the protein kinase and phosphatase profiles at the PSD, to maintain synaptic integrity and function.

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