Alzheimer's disease and age-related memory decline (preclinical)

Abstract

An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD, MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy, adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function.

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

“…In addition, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Namenda ® ) is also used. [9][10][11] However, none of these therapeutic options represent a real cure.…”

“…[9][10][11][12] However, as AD progresses, the activity of AChE decreases, while that of BuChE significantly increases and may even surpass the AChE activity. 13,14 The acetylcholine binding site of AChE is located at the base of a deep hydrophobic channel measuring approximately 20 Å in length.…”

“…In addition, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Namenda ® ) is also used. [9][10][11] However, none of these therapeutic options represent a real cure.The cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are enzymes which are found in the central nervous system (CNS) and catalyze the hydrolysis of ACh efficiently but at different rates. [9][10][11][12] However, as AD progresses, the activity of AChE decreases, while that of BuChE significantly increases and may even surpass the AChE activity.…”

Identification of Small Molecule Memapsin Inhibitors via Computation-based Virtual Screening

“…In reality, cholinergic deficit and Aβ levels correlate well in the disease state [16,17]. Memantine (an NMDA receptor antagonist) apart, all current FDA-approved therapies for the symptomatic treatment of AD are acetylcholine esterase inhibitors (AChEIs) [18][19]. However, most of the clinical efficacy observed in AD is largely restricted to the first two years from inception of treatment.…”

“…However, most of the clinical efficacy observed in AD is largely restricted to the first two years from inception of treatment. Moreover, AChEIs have a number of undesirable side effects, including nausea, sweating, salivation and gastrointestinal disturbances [13,[18][19]. Therefore, there remains a significant need for treatments with less side effect potential, or, preferably, treatments targeting AD progression.…”