The extracellular deposits of of the amyloid beta (Aβ) protein are the hallmarks of Alzheimer's disease(AD) brain. These Aβ deposits are result of-

1) increased production of Aβ (anabolism)- High activity and levels of β-secretase (BACE1) and γ-secretase
(presenilins) increase the amyloidogenic processing of Amyloid Precursor Protein (APP), leading to the increased production of Aβ AND/OR

2) decreased clearance of Aβ (catabolism)- Low activity and levels of various Aβ-degrading enzymes such as Neprilysin (NEP), Insulin degrading enzyme (IDE), MMPs etc. and also of Aβ transporters on blood brain barrier e.g. low-density lipoprotein receptor-related protein 1 (LRP1) causes increased deposition of Aβ in brain leading to plaque formation.

The question arises which of these pathways offer the best potential targets for the therapeutic intervention in AD.

Until now, the focus has been always on the former pathway, Aβ anabloism; there are number of pharmaceutical companies working on this and numerous molecules that inhibit BACE1 and γ-secretases are in clinical trials. However, various recently published reports point toward a beneficial, physiological role Aβ in memory. In this context, in vitro and in vivo studies have shown that increased Abeta production is a result of higher synaptic activity [1,2].

Moreover, in humans undergoing invasive monitoring for acute brain injury, Aβ levels in brain interstitial fluid were found to be strongly correlated with neurological status; Aβ levels decreased as patients declined and increased as they improved [3]. Thus, increased Aβ production may suggest a compensatory mechanism against neuronal damage associated with the disease. These data emphasize the beneficial role of Aβ, which is further supported by a very recent report that at physiological levels (picomolar levels) Aβenhances memory [4]. Thus, inhibition of Aβ production in itself may not offer any therapeutic benefits and may even worsen the disease.

Despite this, there is no question that Aβ aggregates found in AD brain are the culprits behind the AD-associated brain damage. Taken together, all these findings may suggest that the AD-associated damage is inflicted not because of the increased production of Aβ, but possibly by the decreased clearance of Aβ from the brain and hence forming the deleterious Aβ plaques in the brain. Thus, Aβ catabolism may offer novel, effective mechanisms to tackle AD. The upregulation of levels/ activities of NEP, IDE etc. by pharmacological and/or molecular biological means may offer the disease-modifying therapy that is urgently needed to tackle this devastating disease.

In the following post we will look at some significant progress done regarding the Aβ catabolic pathways!

References:

1) Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R. APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37.

2) Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005 Dec 22;48(6):913-22.

3) Brody DL, Magnoni S, Schwetye KE, Spinner ML, Esparza TJ, Stocchetti N, Zipfel GJ, Holtzmann DM. Amyloid-beta Dynamics Correlate with Neurological Status in the Injured Human Brain. Science. 29 August 2008;321:1221-1224.

4) Daniela Puzzo, Lucia Privitera, Elena Leznik, Mauro Fà, Agnieszka Staniszewski, Agostino Palmeri, and Ottavio Arancio. Picomolar Amyloid-β Positively Modulates Synaptic Plasticity and Memory in Hippocampus. J. Neurosci. 2008 28: 14537-14545