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Developing Novel Polymer-mediated Technology for Transfecting Primary Neurons to Study Neurodegenerative Disease


Neurons are post-mitotic cells that are important for learning and memory. Neurons communicate with each other via chemical neurotransmission at a specialized cellular site called the synapse. Neurotransmitters are small molecule ligands that, when released by a pre-synaptic neuron, act on the post-synaptic neuron in either an excitatory or inhibitory fashion depending on the nature of the neurotransmitter. Increases in synaptic strength lead to increased communication between two neurons or long-term potentiation (LTP). Decreases in synaptic strength lead to decreased communication between two neurons or long-term depression (LTD). These changes in synaptic plasticity regulate healthy synaptic function. Disruption of synaptic communication has been shown to lead to deficits in learning and memory, and has become an area of intense research for investigating neurodegenerative disease pathology.

Alzheimer’s disease (AD) is a devastating neurodegenerative disease that affects millions of people worldwide with no cure. Accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles, the two hallmark lesions in a typical AD brain, are comprised of aggregated beta-amyloid and hyperphosphorylated tau (p-tau), respectively. Oligomers of beta-amyloid and tau are believed to be the pathogenic species and most relevant to the disease development and progression. Accumulation of these proteins is associated with disrupted synaptic function and subsequent neuronal death. The Chambers laboratory at University of Massachusetts Amherst is researching overexpression of an enzyme found in AD brains that may contribute to the accumulation of beta-amyloid plaques and hyperphosphorylated tau. Understanding the underlying molecular mechanisms that lead to synaptic dysfunction in AD will enable better treatment and prevention of the progression of this devastating disease. However, primary neurons are post-mitotic and notoriously difficult to transfect using traditional methods, such as calcium phosphate and liposomal-based gene delivery.

Kathryne A. Medeiros (ICE IGERT trainee, MCB, Chambers lab) sought the expertise from the Tew laboratory (Polymer Science & Engineering) at the University of Massachusetts Amherst to pioneer polymer-mediated neuron transfections using a series of novel polymers developed by the Tew laboratory. Mederios developed a method for successfully transfecting primary neurons using polymer-mediated technology and these novel polymers. Primary hippocampal neurons were successfully transfected with a green fluorescent protein (GFP)-encoding plasmid using these novel polymers (see Figure 1). Medeiros determined that using these novel polymers, polymer-mediated transfections showed minimal toxicity and were effective at gene delivery. Further experiments are aimed at increasing polymer-mediated transfection efficiency and comparing neuron transfections using commercially available polymers versus novel polymers in primary hippocampal neurons. Once these experiments are optimized, novel polymers will be used to transfect neurons with our gene of interest. This technology will enable us to study the role of an enzyme that may contribute to the accumulation of beta-amyloid plaques, hyperphosphorylated tau and synaptic dysfunction in Alzheimer’s disease.

Address Goals

A significant obstacle in studying neurons is the ability to deliver genes of interest efficiently. An interdisciplinary team from the Chambers (Chemistry) and Tew (Polymer Science & Engineering) laboratories is combining polymer-mediated technology with molecular biology techniques to deliver genes of interest to primary neurons. This achievement addresses a discovery goal. Further development of this technology may enable efficient gene delivery and expression, allowing the investigation of genes of interest in primary neurons. Additionally, this work supports research infrastructure. Advancement in gene delivery in neurons will be an invaluable experimental tool that allows researchers to investigate the role of genes of interest in neurodegenerative disease pathology.