Alzheimer’s Disease: From Investigative Challenges to Therapeutic Opportunities

	Director: Lennart Mucke, M.D. Joseph B. Martin Distinguished Professor Department of Neurology University of California, San Francisco

Alzheimer's disease (AD) results in a progressive dementia and an inexorable loss of neurons in the brain. Available treatments aim to improve the communication between surviving brain cells, a process that is also impaired by AD. Sadly, none of these treat­ments reproducibly halts or reverses the disease once it has de­clared itself clinically.

Brain cells communicate with each other through the release and receipt of chemical “messengers” called neurotransmitters. Most currently available drugs for AD counteract the AD-associated depletion of the neurotransmitter acetylcholine by preventing its enzymatic breakdown. The recently approved drug memantine prevents over-stimulation of brain cells by blocking receptors for the excitatory neurotransmitter glutamate. Although these drugs seem to benefit some AD patients, their overall impact on the pro­gression of the disease is marginal at best.

While retrospective reviews suggest that long-term consumption of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibu­profen, lowers AD risk, prospective trials have so far been mostly disappointing. Many physicians now recommend regular mental and physical exercise combined with daily doses of an NSAID and one or more vitamins for the prevention of AD, but it will likely take several more years before the real value of these inter­ventions can be ascertained.

Since the benefits of symptomatic treatments are so limited, it is critical to develop much more powerful therapeutic strategies that are aimed at the root causes of the disease. Groundbreaking genet­ic studies have established that AD has more than one cause. Any one of many different mutations in three genes (APP, PS1, and PS2) can cause rare early-onset autosomal dominant forms of AD, most likely by increasing the production of the amyloid-ß peptide (Aß) in the brain. Inheriting the E4 variant of apoE increases the susceptibility to these mutations and to the much more common late-onset forms of AD. Environmental factors such as head trauma can also increase AD risk, particularly when combined with genetic risk factors such as apoE4.

To pinpoint which of these factors constitute the most promising therapeutic targets, investigators at the Gladstone Institute of Neurological Disease (GIND) have generated a number of mechanistically informative transgenic mouse models of AD that are ideal for the preclinical assessment of novel AD treatments. Analysis of these models has highlighted the pathogenic importance of small neurotoxic Aß assemblies, identified potential markers and mediators of Aß-induced neuronal deficits, and revealed potential mechanisms by which apoE4 increases AD risk. New drug targets that have emerged from these studies include components of calcium-dependent signaling pathways as well as such proteases as cathepsin B and a novel apoE-cleaving enzyme.

The accumulation of proteins that have assumed abnormal conformational states appears to play a causal role in most, if not all, neurodegenerative diseases. AD is a “polyproteinopathy,” combining the accumulation of pathogenic fragments derived from the Aß precursor protein (APP) and of apoE with the accumulation of asynuclein and abnormally phosphorylated tau. Although many questions remain about the pathways that lead from the build-up of these proteins to cognitive decline, the prevention and removal of protein accumulations has be­come a major goal in the development of new treatments.

Some of the most promising drugs that are under development or in early clinical trials inhibit enzymes that release Aß from APP, phosphorylate tau, or cleave apoE into neurotoxic fragments. Another category of drugs blocks the assembly of Aß into neurotoxic aggregates. Immunization against Aß can clear these aggregates from the brain, but also elicits pathological inflammatory reactions in a minority of patients. Efforts are under way to make this approach safer. The body produces several enzymes that can degrade Aß, and several strategies are being pursued to increase their activity in the brain.

Other therapeutic initiatives, several of them under way at the GIND, aim to block or counteract the diverse pathogenic cascades triggered by the accumulation of abnormal proteins. Some investigational drugs prevent oxidative damage to proteins and lipids, while others inhibit enzymes involved in cell death programs. A different group of compounds aims to normalize the function of impaired neural circuits by modulating neurotransmitter receptors and calcium-dependent signaling pathways. Complementary preclinical efforts focus on gene therapy, stem cell research, and the delivery of growth factors to repair or replace neural circuits that have been broken through the loss of neurons or their processes.

The identification and rational pursuit of multiple therapeutic targets give reason for hope and optimism. However, it takes a great deal of time, effort, and money to translate promising scientific discoveries into pills that are effective and safe when given to many people with diverse genetic backgrounds. To accelerate this translation process, we also need better biomarkers for AD and more information on the complex interactions between genetic and environmental factors that result in this condition. Expansion of multidisciplinary research efforts in this area could help exploit the therapeutic opportunities that have already been uncovered, in many cases aided by basic research conducted at Gladstone , and shed light on those aspects of AD that remain shrouded in mystery. Our investigators look forward to intensifying their fight against AD and other devastating diseases of the nervous system in Gladstone 's new research facility at San Francisco 's burgeoning Mission Bay campus.