222 Chapter 8
are risk factors for Alzheimer’s disease), and eat a diet rich in
fruits and vegetables to provide antioxidants.Synaptic Changes in Memory
Short-term memory may involve the establishment of
recurrent (or reverberating ) circuits of neuronal activ-
ity. This is where neurons synapse with each other to form
a circular path, so that the last neuron to be activated then
stimulates the first neuron. A neural circuit of recurrent, or
reverberating, activity may thus be maintained for a period of
time. These reverberating circuits have been used to explain
the neuronal basis of working memory, the ability to hold a
memory (of a grocery list, for example) in mind for a rela-
tively short period of time.
Long-term memory (unlike short-term memory) is not dis-
rupted by electroconvulsive shock therapy, suggesting that the con-
solidation of memory depends on relatively permanent changes
in neurons and synapses. This is supported by evidence that pro-
tein synthesis is required for the consolidation of the “memory
trace.” The nature of the synaptic changes involved in memory
storage has been studied in the hippocampus using the processes
of long-term potentiation (LTP) and long-term depression (LTD),
described in chapter 7, section 7.7. The NMDA receptor for gluta-
mate is central to these processes and to the formation of memo-
ries that depend on the hippocampus.
ln long-term potentiation (LTP), synapses that are stimulated
at high frequency exhibit subsequent increased excitability. Long-
term potentiation has been studied extensively in the hippocam-
pus, where most of the axons use glutamate as a neurotransmitter.
Here, LTP is induced by the activation of the NMDA receptors
for glutamate (chapter 7, section 7.6). At the resting membrane
potential, the NMDA pore is blocked by a Mg^2 1 ion that does not
allow the entry of Ca^2 1 , even when glutamate is present. In order
for glutamate to activate its NMDA receptors, the membrane must
also become partially depolarized, causing the Mg^2 1 to leave the
pore. This depolarization could be produced by glutamate binding
to its AMPA receptors ( fig. 8.16 ), but a recent report suggests that
D-serine released from astrocytes might also serve this function
and be needed for LTP. Under these conditions, glutamate binding
to its NMDA receptor causes the NMDA channel to be open so
that Ca^2 1 can diffuse into the cell.
The Ca^2 1 entering through the NMDA receptors binds to
calmodulin, a regulatory protein important for the second-
messenger function of Ca^2 1. This Ca^2 1 -calmodulin complex
then activates a previously inactive enzyme called CaMKII
(calmodulin-dependent protein kinase II). The activated
CaMKII moves to the synapse and phosphorylates proteins that
(1) allow more AMPA receptors for glutamate to be inserted
into the postsynaptic membrane, and (2) increase the ion con-
ductance of each AMPA channel. These events of LTP are spe-
cific to that stimulated synapse, located on a specific dendritic
spine (discussed shortly). As a result, synaptic transmission at
that synapse is strengthened so that a given amount of gluta-
mate produces a greater postsynaptic depolarization (EPSP).In Alzheimer’s disease, an amyloid precursor protein (abbre-
viated APP ) may be broken down by b -secretase and then
g -secretase into peptides called amyloid beta (A b ). The A b pep-
tides can associate into dimers and oligomers, and then grow into
fibers in the form of b -pleated sheets (chapter 2; see fig. 2.28 c )
that compose the amyloid senile plaques. Evidence suggests that
it is the soluble dimers and oligomers of the 42-amino-acid-long
form of A b , more than the plaques, that promote Alzheimer’s
disease. A small proportion (less than 1%) of people with early-
onset Alzheimer’s disease have mutations in the gene for APP
or in presenilin genes that code for the catalytic portion of the
g -secretase enzyme. The vast majority of people with Alzheim-
er’s have the “sporadic” form, caused by incompletely under-
stood interactions between environmental and genetic influences.
Although A b oligomers are themselves toxic, their full abil-
ity to cause Alzheimer’s disease may depend on another protein,
called tau. Normal tau proteins bind to and stabilize microtu-
bules in axons; in Alzheimer’s disease they become excessively
phosphorylated and redistributed to the neuron cell body and
dendrites. There they aggregate together and become insoluble,
forming the neurofibrillary tangles. These changes appear to
be driven by A b. It is evidently not the neurofibrillary tangles,
but rather the more soluble intermediate forms of tau that may
produce the toxic effects. Toxic changes in Alzheimer’s disease
include the loss of synapses and dendritic spines, reduced ability
to produce long-term potentiation (LTP), excitotoxicity (chap-
ter 7, section 7) causing neuron apoptosis, and mitochondrial
release of reactive oxygen species that produce oxidative stress
and apoptosis.
Astrocytes are a major source in the brain of apolipo-
protein E ( APOE ), a protein that caries lipids from degen-
erating neurons and performs other functions important for
neural activity. For reasons not fully understood, people with
the allele for one form of this carrier, APOE4, but not for
the other variants (APOE2 and APOE3), are more likely to
develop sporadic, late-onset Alzheimer’s disease, the most
common form. One recent report suggests that APOE4, but
not the other forms, promotes inflammatory damage to the
blood-brain barrier that may contribute to Alzheimer’s dis-
ease. A single copy of the gene for APOE4 increases the
risk of Alzheimer’s disease by a factor of 4, and two copies
increase the risk by a factor of 19. At this time, the gene for
APOE4 is the major known risk factor for developing late-
onset Alzheimer’s disease.
Currently available drugs for treating Alzheimer’s disease
include (1) inhibitors of acetylcholinesterase (so that ACh
released by the surviving cholinergic neurons can be more
effective); (2) an antagonist of glutamate (to reduce its ability
to promote excitotoxicity); and (3) drugs for treating depres-
sion. A variety of other medications that exploit our growing
understanding of Alzheimer’s disease are currently in clinical
trials. Meanwhile, people are advised to engage in both mental
and physical activity (to build up a “cognitive reserve” and to
promote neuron health), eat a diet restricted in calories and fat
(because obesity, high plasma cholesterol, and type 2 diabetes