Neurotransmitter depletion may be a cause of dementia pathology rather than an effect

Abstract

There is widespread loss of acetylcholine and other neurotransmitters in Alzheimer's disease and vascular dementia. It has generally been assumed that death of neurons causes neurotransmitter loss, but alternatively neurotransmitter depletion itself may at least contribute to neurodegeneration. Transgenic mice and pigs with inducible 50% depletion of acetylcholine, dopamine, norepinephrine, serotonin, gamma-aminobutyric acid (GABA) and corticotrophin releasing factor will reproduce Alzheimer's disease or vascular dementia neuropathology, and pharmacologically restoring neurotransmitters will attenuate neuronal injury. Through nuclear transfer cloning, transgenic mice and pigs would be created with transgenes on one X chromosome, so that transgenes would only be expressed in half of all cells in female animals. Transgenes would encode tetracycline-inducible short hairpin RNA (shRNA) designed to form small interfering RNA (siRNA) to knock down neurotransmitter biosynthesis in late adulthood. Transgene expressing neurons could be readily identified in tissue sections with fluorescent reporter genes. Cholinesterase inhibitors, antidepressants, benzodiazepines and CRF would then be administered in an attempt to rescue degenerating neurons. The mice and pigs could serve as an important new model for the pathogenesis of dementia, especially if pharmacologically restoring neurotransmitters rescues degenerating neurons. The animals may also be useful for as models for other disorders such as multi-system atrophy, Parkinson's disease, and depression.