6 2
chapter
4
Three-Dimensional Structure of Proteins
i l(,( HI 4 14
Section of cerebral cortex from a patient with Alzheimer's disease containing neurofibrillary tangle (A) and neuritic
plaque (B). The section was processed with Bielschowsky's stain. (Courtesy of John M. Hardman.)
to
stabilize
microtubules
in
neurons
by
enhancing
polymerization of
tubulin.
Normally, tau protein is soluble;
however, when it is excessively phosphorylated, it turns
into an insoluble filamentous polymer. The dysregulation
of phosphorylation/dephosphorylation events has been at-
tributed to an enhanced activity of certain kinases and
a diminished activity of certain phosphatases. Whereas
plaques are pathognomonic for AD, tangles are found in
etiologically different neurological diseases. Disorders of
abnormal hyperphosphorylation and aberrant aggregation
of tau protein into fibrillar polymers are known as
tau-
pathies.
Examples of taupathies in addition to AD are
pro-
gressive supranuclear palsy, Pick’s disease, corticobasal
degeneration, and frontotemporal dementias.
Two other genes in addition to /3APP have been impli-
cated in the early onset of autosomal dominant forms of
Alzheimer’s disease. The other two causative genes are
located on chromosomes 14 and 1
and code for trans-
membrane proteins
presenilin 1
(consisting of 467 amino
acid residues) and
presenilin 2
(consisting of 448 amino
acid residues). These proteins are synthesized in neurons
but their functions are not known. However, mutations in
the presenilin genes lead to excessive production of
A f 42
peptides.
Sporadic forms of Alzheimer’s disease, responsible for
90% of all cases, are complex diseases and may repre-
sent the combined action of both environmental factors
and genetic traits that manifest over long time spans. Var-
ious forms of a polymorphic gene for
apolipoprotein E
(apo E) which is on chromosome 19 have been found to
occur in higher frequency in persons with Alzheimer’s
disease. There are three alleles of the apo E gene with
six combinations:
s2/s2, e3/e3, s4/e4, s2/s3, s2/s4,
and
e3/e4.
Apo E is a lipid carrier protein that is primarily
synthesized in the liver; however it is also synthesized in
astrocytes and neurons. The function of apo E proteins
in lipoprotein metabolism and their relation to premature
atherosclerosis are discussed in Chapter 20.
Of the several genotypes for apo E, the acquisition of
two apo E
£•4
alleles may increase the risk for Alzheimer’s
disease up to eightfold. Each copy of the apo E gene in-
creases the risk and shifts the onset to lower ages. The
biochemical mechanism by which apo E
s4
protein par-
ticipates in formation of tangles and plaques is unclear.
Several mechanisms have been suggested, namely, inter-
action with tau protein and generation, and clearance of
Af3
peptides.
Pharmacological therapy for Alzheimer’s disease con-
sists of correcting the
cholinergic deficit
by administering
acetylcholinesterase inhibitors
(e.g., tacrine, donepezil).
Estrogen therapy
in women with Alzheimer’s disease has
been associated with improved cognitive performance.
Estrogen’s beneficial effect may be due to cholinergic
and neurotrophic actions. Other therapeutic strategies are
