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The NMDA receptor: a key junction point in Alzheimer's disease
Lane Simonian
Posted: Friday, March 31, 2017 10:18 AM
Joined: 12/12/2011
Posts: 4863


The activation of protein kinase C alpha leads to NMDA receptor activation early in Alzheimer's disease. Many factors activate protein kinase C alpha including environmental toxins, psychological stress, and various forms of amyloid.  Without the initial activation of protein kinase C alpha there is no Alzheimer's disease.

"Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active."

The NMDA receptor is the key junction point in Alzheimer's disease. Activation of NMDA receptors via the phosphatidyinositol 3-kinase/Akt pathway leads to normal blood flow in the brain, the maintenance of antioxidants in the brain, and the regeneration of neurons in the brain.  Activation of NMDA receptors also leads to the formation of peroxynitrite, caspase 3 activation, and DNA damage which leads to the loss of neurotransmitters needed for the retrieval of short-term memory, sleep, mood, social recognition, and alertness, cause mitochondrial dysfunction and the loss of cellular energy, and the death of neurons. In a non-Alzheimer's brain this split function protects against both cancer (too much cell growth) and neurodegeneration.

Synaptic NMDARs are neuroprotective, and their activity triggers different neuroprotective signaling pathways, such as activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, activation of nuclear CREB (cAMP response element-binding protein), and enhancement of the antioxidant defense system (Hardingham, 2009). Extrasynaptic NMDARs preferentially initiate lethal downstream reactions including mitochondrial dysfunction (Murphy and Fiskum, 1999Wang et al., 1999), oxidative stress (Kinouchi et al., 1991), and nitrosative stress (Aarts et al., 2003Uehara et al., 2006Luo and Zhu, 2011).

But in Alzheimer's disease, oxidation and nitration inhibits the phosphatidyinositol 3- kinase as the disease progresses.  Thus the pathway initiated by NMDA receptor activation (first by protein kinase C alpha and later when this enzymes activity declines by excess amounts of glutamate) becomes solely one of neuronal cell death rather than of neuronal cell survival.  

"The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway."

The key to the treatment of Alzheimer's disease thus becomes limiting the formation of oxidants and removing oxidants produced through the activation of NMDA receptors.

"We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis."