Theory of Alzheimer's Disease
My work on the role of acetylcholine in memory function has implications for Alzheimer's disease. The primary drugs being used for treatment of Alzheimer's disease are acetylcholinesterase inhibitors, which increase levels of acetylcholine by reducing the enzymatic breakdown of acetylcholine.
My physiological work and modeling work indicates how acetylcholine regulates the cellular effects important for episodic memory function.
My modeling work suggests how the initiation and progression of neuropathology in Alzheimer's disease might start in regions associated with memory function, and progress to other cortical regions via functional pathways.
In computational models of cortical function, recall of previously
stored memories during storage of new memories can result in runaway
synaptic modification, in which a large number of synapses are
strengthened within the network. In an early article
(Hasselmo, 1994), I proposed that runaway synaptic
modification could underlie the initiation and progression of
neuropathology in Alzheimer's disease. This pathology starts in
subregions of the hippocampal formation which have a strong capacity
for synaptic modification, and hence a greater sensitivity to
runaway synaptic modification. Cholinergic suppression of synaptic
transmission during learning of new information can prevent runaway
synaptic modification, whereas loss of this cholinergic modulation
could speed the progression of runaway synaptic modification.
(Further description.).
The figure shows the matrix of excitatory synaptic connectivity
between 240 pyramidal cells in a biophysical simulation of the
piriform cortex (using the GENESIS simulation package). When learning
occurs without cholinergic suppression of synaptic transmission,
(Without ACh), runaway synaptic modification results in strengthening
of a large number of synapses. When
learning occurs with cholinergic suppression of synaptic transmission,
(With Ach) effective associative memory function is obtained. Thus, the process of runaway synaptic modification can be retarded by selective regulation of synaptic transmission. This could be obtained with pharmacological agents selectively targeting presynaptic heteroreceptors regulating glutamatergic transmission. Similarly, the process can be slowed by blockade of synaptic modification. The slowing of runaway synaptic modification through blockade of synaptic modification could underlie the clinical efficacy of the NMDA antagonist memantine for treatment of Alzheimer's disease.
