Biomedical Engineering Reference
In-Depth Information
Four medications are currently approved by regulatory agencies such as the
US Food and Drug Administration (FDA) and the European Medicines
Agency (EMEA) to treat the cognitive manifestations of AD. Three are
acetylcholinesterase inhibitors (Aricept, galantamine and rivastigmine) and the
other is memantine, an NMDA receptor antagonist. No drug has an indication
for delaying or halting the progression of the disease.
Aricept, galantamine and rivastigmine work by enhancing cholinergic
function. This is accomplished by increasing the concentration of acetylcholine
through reversible inhibition of its hydrolysis by acetylcholinesterase.
Memantine acts on the glutamatergic system by blocking NMDA glutamate
receptors and blocks the toxic effects associated with excess glutamate and
regulates glutamate activation. New drugs still in trials such as Bapineuzumab,
Solanezumab, Gammagard are antibodies against amyloid (the first two lab-
made and the last one culled from blood) and extremely expensive.
Cytotoxic effects of Ab interactions with neuron cells are expressed by the
accumulation on ganglioside and cholesterol-rich domains of cell membranes
demonstrating localized neurite degeneration prior to induced cell death, loss of
Ca
21
homeostasis, which may result from changes in endogenous ion transport
systems (e.g. Ca
21
and K
1
channels and Na
1
/K
1
-ATPase) and membrane
receptor proteins, such as ligand-driven ion channels and G-protein driven
releases of second messengers, or the formation of heterogeneous ion channels.
These changes in membrane transport systems are proposed to impair neuronal
function by compromising membrane integrity and increasing its ion permea-
bility. Other cytotoxic effects are represented by the generation of reactive
oxygen species leading to peroxidation of phospholipids in the membrane,
inhibition of phosphorylation, and reduction of ATP levels and cytoplasmic
pH, and reduced cellular reductase activity (a measure of cellular viability). The
treatments are plagued by side effects (brain edema, cardiovascular, gastroin-
testinal, etc.), which sometimes determine the immediate cessation of treatment
in order to spare the patient's life.
Soluble oligomers of Ab are considered to be one of the major contributing
factors to the development of AD. Most therapeutic development studies have
focused on toxicity directly at the synapse. Soluble Ab can also cause functional
toxicity; namely it inhibits spontaneous firing of hippocampal neurons without
significant cell death at low concentrations. This toxicity eventually leads to the
loss of synapses as well, but the effect on function may precede this loss by a
considerable amount of time.
One of the characteristic symptoms of AD is the impairment of memory
function. Although memory mechanisms are still not well understood, two
processes—long-term potentiation (LTP) and long-term depression
(LTD)—are thought to be opposing forces that are responsible for memory
storage. Ab oligomers inhibit LTP, enhance LTD and reduce dendritic density
in the normal hippocampus. The toxic effects of Ab oligomers were demon-
strated by using cultured hippocampal neurons on an MEA, confirming
previous data from patch clamp studies. Using multielectrode arrays this process
can be investigated in a very elegant way, as described by Varghese et al.
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