Editorial [Hot topic: Alzheimer's Disease Drug Discovery: Aβ and Beyond (Guest Editors: D.W. Shineman and H.M. Fillit)]

Alzheimer's disease (AD) drug discovery researchers face immense challenges in developing drugs that get into the brain, are safe and ultimately produce clinically meaningful results. Perhaps even more challenging is determining at what point in the disease cascade is best to intervene. We know that many different pathways initiate or exacerbate disease progression [1]. Amyloid-β (Aβ), the main component of amyloid plaques, has long been considered the leading target for AD intervention programs even though the amyloid cascade hypothesis remains controversial to this day [2, 3]. Innovative approaches to target Aβ are being developed and may be the best way to treat the disease at its earliest stages. Yet, as we learn more about the disease, it is becoming increasingly clear that alternative approaches may also be necessary to diversify the AD drug discovery portfolio. Increasing “shots on goal” will bring new ideas and novel targets into the pipeline, accelerating treatment development for AD.

In the spirit of these objectives, the Alzheimer's Drug Discovery Foundation (ADDF) hosted the 10th International Conference on Alzheimer's Drug Discovery on September 14-15, 2009 in Jersey City, NJ. At the conference, attendees were treated not only to the breathtaking skyline view of New York City, but also to two days of diverse research aimed at AD drug discovery. The conference drew attendants from academia, industry and government. Sessions focused on Neuroprotection Strategies (chaired by Frank Longo, Stanford University), Anti-Amyloid and Protein Misfolding (chaired by Michael Wolf, Harvard Medical School), Anti- Tangles and Frontotemporal Dementia (chaired by Jeff Kuret, Ohio State University), and Alternative Strategies: New Targets for AD Therapy (chaired by Diana Shineman, ADDF). A comprehensive summary of the conference can be found on the conference web site (http:// www.worldeventsforum.com/addf/10th/html/summary.html) . The proceedings in this special issue highlight a few of exciting programs presented at this conference. This year's conference built upon previous efforts and focused more heavily on alternative targets for therapeutic development [4-6].

The ultimate goal for AD drug discovery, regardless of the molecular target, is to protect neurons and their processes so that memory and function can be maintained. There are many ways to target neuroprotection and strengthen neuronal defenses against the toxic insults of AD. For example, Karin Yurko-Mauro from Martek Biosciences presents an overview of clinical data on the health benefits of Docosahexaenoic acid (DHA), the main component of omega-3 fatty acids (Yurko-Mauro, page 190-196). Her paper notes that DHA supplementation resulted in a cardiovascular benefit (decreased heart rate, blood pressure and triglycerides) as well as some cognitive benefit in older individuals with memory complaints, specifically in the paired associated learning test. Still, further studies are needed to determine if DHA substantially impacts AD progression.

It is easy to lose sight of the big picture when the field is often focused narrowly on specific molecular targets. In this issue, Michela Gallagher (Johns Hopkins University) reminds us that AD is a disease of neuronal systems, underlined by synaptic failure that begins very early in the disease process (Gallagher et al., page 197-199). This paper shows evidence that hyperactivity in the CA3 region of the hippocampus, the brain region critical for proper memory function, precedes memory deficits in animal models as well as in humans. Therapeutic development efforts are focused on inhibiting this hyperactivity to hopefully prevent downstream synaptic degeneration, memory loss and pathology seen in later stages of AD.

Echoing the sentiments of Dr. Gallagher, James Malter (University of Wisconsin) also looks at AD as a systemsbased disease and presents work on the Fragile X Mental Retardation Protein (FMRP), which has recently been shown to regulate the dendritic translation of APP downstream of mGluR5 activation (Malter et al., page 200-206). mGluR5 antagonists can decrease Amyloid Precursor Protein (APP) translation and reduce Aβ40 in brain lysate. Work is ongoing to expand on these findings.

While Dr. Malter's program targets upstream of Aβ generation at the level of APP, Michael Wolfe (Harvard Medical School), Philip Williams (University of Hawaii) and Michael Sierks (Arizona State University) are all focused on intervening directly at the level Aβ generation using very different approaches. In these proceedings, Dr. Wolfe presents a summary of the discovery and development of inhibitors of γ-secretase that block Aβ generation while sparing Notch to prevent the side effects seen with pan γ- secretase inhibition (Augelli-Szafran et al., page 207-209)...