Biomedical Engineering Reference
In-Depth Information
the AD brain, as this rel ects a massive degeneration of cholinergic neurons. However, since the loss
of cholinergic markers is a relatively a delayed event in the development of AD and since subse-
quent studies failed to demonstrate a causal relationship between cholinergic dysfunction and AD
progression, the “cholinergic hypothesis” was abandoned as an explanation of AD's pathogenesis.
Instead, it seems that the aberrant production and deposition of plaques and tangles in AD is not
only a disease marker, as the pathways leading to the formation of these aggregates seem to play
a causal role in the pathogenesis of AD. At present, the “amyloid cascade theory” is the dominant
etiological paradigm in the AD i eld, and the theory is supported by a substantial amount of his-
topathological, biochemical, genetic, and animal model data. However, it is still debated whether
the tau tangles or the amyloid plaques are the primary cause of the neurodegeneration in AD, and
the links between the b-amyloid and tau and between the formation of plaques and tangles in the
disease are still elusive.
The complexity of the etiology of AD is rel ected in the numerous strategies applied over the
years in the attempts to develop clinical efi cacious drugs against the disorder. The formulation of
the “cholinergic hypothesis” spawned the clinical testing of drugs targeting the acetylcholine (ACh)
neurotransmitter system in the late 1980-1990s, the overall rationale being to augment cholinergic
signaling to compensate for the degeneration of cholinergic neurons. Four out of i ve drugs cur-
rently approved for clinical treatment of AD are acetylcholinesterase inhibitors (AChEIs), and thus
this drug class still represents the predominant clinical treatment of AD (see the following). In
Figure 16.3 selected structures of noncholinergic ligands studied in the context of AD treatment is
shown. Several potent inhibitors of the two enzymes mediating the formation of the Ab
40/42
peptide,
b-secretase, and g-secretase, have been developed, for example, the g-secretase inhibitors BMS
299897 (
16.1
) and LY-374973 (
16.2
). Other lines of research have focused on the development of
molecules capable of inhibiting the aggregation processes leading to the formation of plaques and
tangles. In view of the excitotoxicity in AD, considerable efforts have been put into the studies of
calcium channel blockers, protease inhibitors, and glutamate receptor antagonists (see Chapter 15),
and the uncompetitive NMDA receptor antagonist memantine (
16.3
) has recently become the i rst
noncholinergic drug for the treatment of AD to be introduced on the market (Namenda
®
). On the
other hand augmentation of AMPA receptor signaling (see Chapter 15) by a class of compounds
COOH
F
CH
3
F
N
O
N
S
O
F
O
F
H
O
O
CH
3
O
F
F
BMS 299897 (
16.1
)
LY-374973 (
16.2
)
NH
2
O
O
N
N
+
N
+
OH
O
O
O
Memantine (
16.3
)
Aniracetam (
16.4
)
Acetylcholine (
16.5
)
Choline (
16.6
)
FIGURE 16.3
Chemical structures of acetylcholine, choline, and some noncholinergic ligands developed
for the treatment of AD.
