Acetylcholine and Memory Defect in Alzheimer's.

One of the characteristic changes that occurs in Alzheimer's disease is the loss of memory and the loss of acetylcholinesterase (AChE) from both cholinergic and noncholinergic neurons of the brain. However, AChE activity is increased around amyloid plaques. ( Sberna, Saez-Valero, Beyreuther, Masters, and Small, 1997 ) This increase in AChE may be of significance for therapeutic strategies using AChE inhibitors.
Amyloid beta-protein (A beta), the major component of amyloid plaques, acts on the expression of AChE. A beta peptides spanning residues 1-40 or 25-35 increased AChE activity in P19 embryonal carcinoma cells. A peptide containing a scrambled A beta ( 25-35 ) sequence did not stimulate AChE expression. Way then an increase in AChE, the increase in AChE expression around amyloid plaques could be due to a disturbance in calcium homeostasis involving the opening of L-type VDCCs. ( Sberna, Saez-Valero, Beyreuther, Masters, Small, 1997 )
The deposit of these beta-amyloid peptides in the brain in form of senile plaque is the key event responsible for Alzheimer pathology. Among various mechanisms that have been proposed to explain the Neuro toxicity of beta-amyloid deposits, beta-amyloid peptides may be indirectly toxic for neurons by activating micro glial cells to produce NO (2). ( Bianchini, 1996 )
The degeneration of the cortex, basal forebrain, and hippocampus, in this way leads to a profound loss of memory.

Acetylcholine receptors are neurotransmitter receptors. Neurotransmitter receptors are proteins that react with extracellular signals, such as acetylcholine, and convert them into intracellular effects (Hucho 1993). They are integral membrane proteins, that is they are within the cell membrane as shown in the figure. ACh receptors are ligand gated ion channels, and they are found on the post synaptic membrane on the target cells.

ACh receptors are one of the chief receptors for excitator neurotransmitters (Alberts et al. 1998). A signal to move a muscle travels from the CNS down a motor neuron to the target muscle cell (www.macalester.edu). The binding of acetylcholine to ACh receptors results in a change in memprane potential of the target cell leading to an action potential in the muscle cell. The acetylcholine is rapidly removed by enzymatic breakdown or reuptake so that when the presynaptic cell stops, the post synaptic cell will stop as well. When the neurotransmitter binds with the receptor, the channel opens and allows Sodium ions into the cell which depolarizes the plasma membrane to create the action potential (Alberts et al. 1998). There are two subtypes of acetlycholine receptors. A predominantly excitatory one in the PNS and another in the autonomic ganglia and CNS. They are typically called muscular and neuronal. There are several subtypes of AChR but the one specified here is the nicotinic AChR. It has two binding sites, and has elaborate pharmacology and toxicology. Because of this, it has been identified, characterized and isolated.