An update on drug treatment options of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by progressive decrease in cognitive function and loss of short-term memory known to be associated with a dysfunction of the cholinergic system. The pathological hallmarks of AD are beta-amyloid (Abeta) plaques and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau. Hypercholesterolemia and disturbances in glucose metabolism are another risk factors. During the last two decades therapeutic strategies were mainly targeting the Abeta hypothesis. As this approach virtually failed to show a significant clinical benefit research on potential therapeutics has been shifted to tau pathology. However, also this approach has as yet not yielded in new therapeutics. Hence, rebalancing the cholinergic input to improve the cognitive symptoms of AD by inhibition of acetylcholine esterase (AChE) is still the only mechanistic target in addition to N-methyl-D-aspartate (NMDA) receptor blockade by memantine that can be addressed by currently approved medications. Despite the fact that the available AChE inhibitors are directed at an identical target they exhibit some pharmacodynamic and pharmacokinetic features that should be considered when used clinically.

Protective effects of NMDA receptor antagonist, memantine, against senescence of PC12 cells: A possible role of nNOS and combined effects with donepezil

“…Memantine has been approved for the treatment of moderate to severe AD in Europe since 2002, in USA since 2003, and in Japan since 2011 (Allgaier and Allgaier, 2014), and has been shown in clinical trials to be a safe and effective treatment for vascular dementia (Orgogozo et al, 2002). Because memantine showed a protective effect on PC12 cells, we then examined its effect on vascular endothelial cells.…”

Being human: The role of pluripotent stem cells in regenerative medicine and humanizing Alzheimer's disease models

“…The first to do so was by Duan et al, who focused on patient lines derived from three ApoE3/E4 AD individuals, as well as two PSEN1 mutant patients (A246E and M146L) and four control patients (Duan et al, 2014). In addition, this was the first study to look at AD iPSC-derived basal forebrain cholinergic neurons (BFCNs), a vulnerable population in AD and the target of cholinesterase inhibitors (Allgaier and Allgaier, 2014). Two of three ApoE3/E4 iPSC-derived BFCNs had enhanced Aβ42/Aβ40 ratios, with one being significantly greater than BFCNs generated from the two PSEN1 cell lines.…”

Neuronal histamine and cognitive symptoms in Alzheimer's disease

“…In addition, they are seemingly only effective during early stages of the disease. More recent therapeutic approaches, based on the amyloid-beta toxicity hypothesis, including immunization strategies, have been essentially ineffective, so that Alzheimer researchers still attempt to refine the existing medications (Allgaier and Allgaier, 2014). Therefore, it is worth exploring novel pharmacological treatments and anatomical targets in order to develop better and alternative medications.…”