Alzheimer's Disease - Treatment

Currently, two medicines for the treatment of Alzheimer's disease (AD) have been approved by U. S. Food and Drug Administration (FDA): cholinesterase inhibitors and NMDA antagonists. Cholinesterase is an enzyme that breaks down the neurotransmitter acetylcholine. Inhibition of this enzyme can preserve acetylcholine. NMDA antagonists block a class of ion channels called NMDA channels which allow calcium ions to enter the neuron. Thus NMDA antagonists aim to reduce overexcitation of neurons. However, the free Tau proteins can still cause other damages by forming tangles (see The Tau Protein). It is not surprising that these medicines have "demonstrated very modest, symptomatic efficacy" (reference).

In the 1990s and early 2000s, beta amyloid (Aβ) was thought to play the central role in AD. Drug development had focused on Aβ. "To date, all AD clinical trials based on Aβ as a therapeutic target have failed" (reference).

Recently, a drug targeting Tau has shown promising results. It is an eight-residue peptide with sequence NAPVSIPQ (one letter symbol). The peptide is called NAP, which is an active fragment in activity-dependent neuroprotective protein (ADNP). ADNP is essential for brain formation. Knockout of both copies of the ADNP gene is lethal to the embryo. Knockout of one copy of the gene increased Tau phosphorylation, resulting in tangle-like structures and neurodegeneration. NAP treatment partially ameliorated cognitive deficits and reduced Tau hyperphosphorylation (reference).

How NAP can reduce Tau hyperphosphorylation is not clear. It has been shown that NAP does not directly affect polymerization or dynamics of reconstituted neural microtubules (reference). Its neuroprotective action may involve cell signaling (reference).

NAP is now known as davunetide, which is in phase II clinical trials developed by Allon Therapeutics.

Author: Frank Lee
Last updated: March 2, 2011