A Looming Crisis

Despite impressive recent advances in the increasingly intertwined fields of clinical neurology and basic neuroscience, Alzheimer’s disease (AD) and related neurological disorders continue to rob people of their ability to remember, speak, ambulate, and control their lives. Each year, more than 50,000 Americans die with AD. Alarmingly, in the U.S. alone, the number of patients suffering from this tragic illness is expected to rise from about 4.5 million today to over 12 million by 2050, threatening not only patients and their families, but also our healthcare system and society in general.

We urgently need to increase the scope and depth of investigations into the mechanisms by which this and related conditions impair and ultimately destroy the brain. Researchers at the Gladstone Institute of Neurological Disease (GIND) are pursuing a range of potential causes and interventions for AD. Key among them is the theory that AD results from the interruption of neuronal networks in the brain by small clusters of sticky protein fragments called amyloid beta peptides, or Aβ for short.

Pathological hallmarks of AD. Amyloid-β peptides (Aβ) self-aggregate and form increasingly larger protein assemblies that accumulate in the brain. The largest of these assemblies (amyloid plaques), a pathological hallmark of the disease, displace neuronal processes and are typically also associated with abnormalities in adjacent neuronal branches (neuritic dystrophy). However, smaller Aβ assemblies (oliogmers and protofibrils) are very difficult to detect but appear to be more neurotoxic, insidiously disrupting neuronal functions and survival. Another pathological hallmark of AD is intraneuronal aggregates of the microtubule-binding protein tau called neurofibrillary tangles. Their formation is promoted by Aβ and by apoE fragments. Even without neurofibrillary tangles, neurotoxic Aβ assemblies can impair synapses, effectively disrupting the communication between brain cells that is essential for cognition and other neurological functions. Memory and other cognitive functions also depend on a number of signaling molecules that mediate neuronal functions and that are depleted in AD.

Building a New Model of AD

Recent research from GIND and a few other leading centers has contributed to an important paradigm shift in the field. Earlier theories focused on large clumps of amyloid called plaques, made up of millions of Aβ molecules, as responsible for the cognitive decline in AD. However, more and more researchers now favor the idea that the real culprits—which are harder to detect than plaques—are much smaller clusters of Aβ. In studies of experimental animals, GIND director Dr. Lennart Mucke and his collaborators have shown that high levels of a soluble form of Aβ disrupt, in plaque-independent fashion, the complex brain circuits in which memories are formed and stored. This finding helps to explain the discrepancies between plaque burden in the brain and cognitive decline in AD that have confused the field for decades.

The black box of AD. While several triggers of the pathogenic Alzheimer cascade have been well defined, the understanding of processes leading from APP, Aβ, and apoE4 to neurodegeneration and cognitive decline is still very limited. The identification of molecular markers and mediators linking these molecules to specific disease manifestations could provide useful outcome measures for clinical trials as well as additional targets for therapeutic intervention.

Emerging Strategies for Prevention and Treatment

This new model has important implications for the treatment of AD. If the model is correct, it might be possible to prevent or eliminate the small clusters of Aβ, thereby avoiding permanent damage to brain cells. AD might be halted at an early stage or even reversed at more advanced stages. As long as their cell bodies are intact, neurons have a remarkable ability to repair the fine processes that form the intricate networks in which information is stored and processed in the brain. Several strategies to expedite the development and preclinical assessment of Aβ-targeted treatments are now being pursued in the laboratories of Drs. Li Gan and Mucke at the GIND. These efforts involve interfering with the small Aβ clusters and their effects before they can wreak havoc on the function of neurons, let alone kill these precious cells.

These studies are complemented by efforts in the laboratories of Drs. Yadong Huang, Robert Mahley, and Karl Weisgraber to manipulate the formation and removal of Aβ through its interaction with the lipid carrier apolipoprotein E (apoE). The E4 variant of apoE—the best-established genetic risk factor for AD—increases the accumulation of Aβ in the brain and is associated with more Aβ-induced neuronal damage than the E3 variant, which protects against AD. Gladstone researchers are developing therapeutic strategies to inhibit this and other disease-promoting effects of apoE4.

Because many people already have a major build-up of Aβ clusters in their brains, often without knowing it, it is important to find ways to protect their neurons against the toxic proteins. Recently, Dr. Mucke and his collaborators identified molecular pathways by which Aβ clusters could impair cognitive functions. AD-related cognitive deficits, they showed, are tightly linked to the depletion of calcium-dependent proteins in memory centers of the brain. These findings provide new surrogate markers for preclinical trials and pinpoint biochemical pathways that could be targeted therapeutically.

Parallel efforts focus on inhibiting the formation of the neurotoxic Aβ clusters and enhancing their removal. Several strategies have recently been developed at companies and academic centers around the world to inhibit the production of Aβ, to interfere with the assembly of Aβ into toxic clusters, or to enhance their removal from the brain. The relative efficacy and safety of several of these strategies are being assessed in experimental models of AD developed in Dr. Mucke’s laboratory.

Dr. Mucke and collaborators at the University of California showed that Aβ can also enhance the accumulation and toxicity of other disease-causing proteins, including β-synuclein, which plays a key role in Parkinson’s disease. Their findings provide a molecular explanation for the frequent clinical and pathological overlap between AD and Parkinson’s disease and suggest that Aβ-targeted therapies might benefit not only people with AD, but also those suffering from related neurodegenerative conditions.

Likely need for combination therapy. Because the etiology of AD is heterogeneous and many drugs have a relatively narrow therapeutic window, the most effective treatment of this disease will likely involve the combination of drugs with mechanistically distinct actions. The advantages of such a strategy have been demonstrated in other multifactorial diseases, for example, hypertension and atherosclerosis. Based on this insight, Gladstone researchers pursue a variety of therapeutic avenues, all of which may ultimately benefit people who already have AD or who are destined to develop the condition unless critical causal chains are broken in time.

Hope for the Future

There is reason for hope that better strategies to treat—and perhaps even prevent—AD could become available in the near future. While the investigation of neurological diseases has promoted basic neuroscientific discoveries for over a century, there has never been a more promising and exciting convergence of basic and disease-related neuroscience than now. However, continued funding is crucial if we are to rapidly exploit all the therapeutic opportunities our research has uncovered.

Most people are sooner or later confronted by this disease, either directly or through a loved one. Since most AD victims are unable to fight for their cause, it behooves all of us to do it for them. GIND scientists will continue to advance the understanding of the nervous system so that better strategies can be developed to protect and repair the fragile structures that harbor the essence of who we are.

Gladstone Contributions to the Fight Against AD Selected Findings Related to Effects of Amyloid Identified the serine protease inhibitor β1-antichymotrypsin as a key modulator of Aβ accumulation in the brain. Increased production of this protein doubles the cerebral amyloid plaque burden in transgenic mice. Demonstrated that high levels of Aβ in the brain are toxic to synapses and result in a severe, plaque- independent disruption of neural memory circuits. Found that Aβ enhances the intraneuronal accumulation of β-synuclein, potentially explaining the frequent overlap between AD and Parkinson’s disease. Demonstrated a tight link between AD-related cognitive deficits and neuronal depletion of calcium- dependent proteins in the dentate gyrus, a brain region critically involved in learning and memory; some of the identified pathways may mediate neuronal dysfunction and are being targeted in ongoing preclinical trials. Observed that eliminating Fyn, an enzyme that regulates the activity of many other proteins, prevents key features of AD in mouse models. Showed that inhibiting cathepsin B prevents Aβ-stimulated inflammatory cells from killing neurons, suggesting a new approach to treating neurodegeneration induced by Aβ and inflammation. Demonstrated that apoE3, but not apoE4, prevents or delays Aβ-induced cognitive deficits and synaptic impairments in mouse models. This finding helps to explain the effects of apoE variants on AD risk (E3β, E4β) and underscores the importance of apoE-targeted drug-development efforts under way at Gladstone.