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Abstract

Citation: Spilman P, Jagodzinska B, Bredesen DE, John V (2015) Enhancement of sAPPα as a Therapeutic Strategy for Alzheimer's and Other Neurodegenerative Diseases. J Alzheimers Neurodegener Dis 1: 001. Introduction Therapeutics for Alzheimer's Disease (AD)The number of cases of Alzheimer's Disease (AD) -the most prevalent age-associated dementia -is expected to increase rapidly as society ages, rising from approximately 5 million at present to 15 million cases by 2050 in the US [1], and currently there are no treatments that prevent onset or alter the course of the disease. AD is a progressive neurodegenerative disorder characterized by the presence of senile plaques, composed mainly of Amyloid β peptide (Aβ) [2,3], and the development of neurofibrillary tangles of hyper-phosphorylated tau (ptau) in brain tissue [4,5]. AD patients suffer from deficits in cognition, learning and memory, and exhibit impaired Long-Term Potentiation (LTP) [6] and a consistent deficit in cholinergic neurotransmission. The currently approved therapeutics include the acetylcholinesterase inhibitors donepezil, galantamine, rivastigmine, and tacrine which inhibit the breakdown of acetylcholine at the neuronal junction, and the N-Methyl-D-Aspartate (NMDA) receptor antagonist memantine, which reduces the excitotoxicity that results from NMDA receptor overstimulation in AD. Recently, the FDA has approved a fixed-dose combination of memantine hydrochloride extended release (Namenda XR) and donepezil hydrochloride (Namzaric) for moderate to severe AD-related dementia. These current therapeutics offer only temporary improvement in cognition and/or delay in progress of the disease, thus there is clearly a need for new approaches to and discovery of new targets for AD therapeutic development.More recent approaches to AD therapeutic development include re-purposing the anti-epileptic drug levetiracetam to address the seizure-like activity manifest in many AD patients [7,8], use of anti-diabetic drugs including intranasal insulin [9,10], and development of BACE inhibitors [11][12][13], including our own APP-selective BACE inhibitors [14], to name a few. It is hoped that some of these new approaches will provide benefit in AD, but it is very likely that truly effective treatment for AD will require multiple therapeutics working in concert -similar to the approach used for AIDS therapy -to address the many deficits in the disease. One component of this multi-modal therapy should restore and promote normal neuronal function, rather than just arrest a single deleterious process underlying the disease. It is our hypothesis and that of others that enhancement of trophic peptide sAPPα, or the activity of the enzyme ADAM10, could play this key role in therapy. Aβ plaques and the amyloid hypothesis in ADThe original evidence pointing to amyloid as causative in AD came from the finding of amyloid plaques in the brains of AD patients. It was ultimately determined that these plaques were comprised of Amyloid-β (Aβ) peptides [15,16] and based on the presenc...