Cholinergic hypothesis
AD is thought to be mediated either directly or indirectly by other processes, too. For instance, the cholinergic system has reigned in a large degree of support through the cholinergic hypothesis.
This hypothesis states that dementia-like behavior is due to a malfunction in the cholinergic system (Dringenberg, 2000; Lahiri et al., 2003; Conway et al., 2003). More specifically, according to Dringenberg, cholinergic nuclei of the basal forebrain, which have projections leading to the cerebral cortex, hippocampus, amygdala, and other forebrain structures, undergo degeneration. The greatest loss of cholinergic activity is seen in the temporal lobe, which houses the hippocampus and entorhinal cortex. It is not surprising that the hippocampus plays an important role in learning and memory, which is also a primary target for degeneration in AD. Figure 3 below shows the linkage between hippocampus, entorhinal cortex and other structures within the cholingeric system.
Figure 3 taken from: http://www.hosppract.com/genetics/0002mmc.htm
The atrophy and loss of basal forebrain nuclei lead to decreases in acetylcholine (ACh) and acetylcholinsterase (AChE). AChE is an important regulator of ACh activity because it degrades ACh in the synapse which helps play a role in stopping ACh’s agonistic properties (Dringenberg, 2000; Lahiri et al., 2003).
AChE has other uniques properties as well. Studies indicate that AChE does not serve a unifunctional role. For instance, it has been discovered that “read-through” and synaptic” variants of AChE exist (Lahiri et al., 2003).
Evidently, the read-though version, AChE-R, increases when a mammal’s brain is exposed to or perceives highly stressful conditions. Researchers now believe that AChE-R hampers, while the synaptic version, AChE-S, increases the likelihood of neurodegeneration following stressful conditions (Lahiri et al., 2003).
In the future, this may play an important role in the pathology, treatment, and prevention of AD, as AChE-R is deemed as capable of preventing acute stress from manifesting into progressive neurological diseases.
In relation to the cholinergic system, it should also be noted that presynaptic cholingergic structures tend to affect cholinergic activity to a greater extent than postsynaptic structures, in relation to AD. In other words, loss of cholinergic neuron projections and presynaptic markers, not postsynaptic receptivity is central to the cholinergic hypothesis (Dringenberg, 2000; Lahiri et al., 2003). With all this in mind, it has become widely accepted that increases in cholinergic activity will subsequently improve memory and cognition in AD.
On the other hand, the cholinergic hypothesis has its critics, too. Dringenberg (2000) felt that the cholinergic system is not a sole cause, rather a factor with interactive properties. Experiments have shown that blocking central cholinergic muscarinic receptors interferes with a rat’s ability to learn spatial locations. However, according to Dringenberg, this is merely a result of behavioral-inhibition rather than a cognitive-inhibition.
More specifically, selective disruption of muscarinic receptors leads to sensorimotor difficulties, which consequently serve as a road block for learning. Furthermore, if these sensorimotor difficulties are compensated for through drug treatment, etc., while at the same time retaining an obstruction of transmission in cholinergic-muscarinic synapses, learning and memory impairments have been shown to be minimal (Dringenberg, 2000).
Until recently, experimental techniques were apt to damaging both the cholinergic system and nearby areas (non-cholinergic areas), which produces confounding effects. However, if damage to the cholinergic system of the basal forebrain is specific enough, cognitive impairments are often lower than what is often cited. This was demonstrated by injecting an immunotoxin, 192 IgG-saporin, into a rat. The highly selective damage brought on by this immunotoxin to the cholingeric system produced minor effects on cognition. Dringenberg (2000) summarized this and some recent studies by stating that an inverse relationship exists between the amount of selective cholinergic system damage and the amount of cognitive performance loss. Thus, higher degrees of selectivity will lead to lower levels of cognitive performance loss.