Dr. Daniel Alkon's laboratory at the Blanchette Rockefeller Neuroscience Institute (patent portfolio now licensed to Neurotrope) conducted multidisciplinary research on the molecular and biophysical mechanisms of associative memory and memory dysfunction in psychiatric and neurological disorders, particularly Alzheimer's disease. Over the years, Dr. Alkon and his colleagues first identified molecular mechanisms of memory that were responsible for classical conditioning of the Mollusk Hermissenda. They then demonstrated that these molecular mechanisms were conserved across evolution, providing a basis for memory-specific changes for synaptic function in a variety of animal species and associative learning paradigms. Subsequently, they have discovered a convergence of memory-specific molecular and synaptic functions with the pathophysiology of Alzheimer's disease, particularly involving biochemical cascades in which the isozymes of PKC play a central role. PKC activators, for example, phosphorylate the mRNA stabilizing proteins (HuD, HuR) during associative learning. The mRNA stabilizing proteins then move into the dendritic tree to stabilize and regulate an ensemble of synaptic remodeling proteins such as GAP43, BDNF, IGF, and NGF. Similarly, memory-specific activation of PKC isozymes activate additional pathways to control learning specific protein synthesis via the NFkB and CREB pathways.
These same pathways are targeted by toxic Beta elevated in Alzheimer's tissues to cause the synaptic loss characteristically demonstrated at autopsy and that correlates with the dementia shown by patients clinically. Thus, the convergence of molecular pathways of memory and the pathologic pathways responsible for neuro-degeneration has provided a whole new strategy for treatment in our aging population. Bryostatin, completed a 148 patient phase 2 trial, has shown remarkable efficacy in preclinical models inducing new synaptic growth in fully differentiated nervous systems, for rescuing dying neurons, and for the normalization of A Beta and amyloid plaques. These new findings on associative memory mechanisms are guiding development of drug discovery with the potential to treat the loss of synapses and to prevent neuronal death in neuro-degenerative disorders such as, Alzheimer's disease, stroke, traumatic brain injury, fragile x, Neimann Pick type C, Rett Syndrome and attention-deficit disorders.