September/October 2013

Pharmacological Prospects
for Alzheimer’s Treatment

By Norbert Myslinski, PhD
Today’s Geriatric Medicine
Vol. 6 No. 5 P. 10

Last year saw the failure of two major Alzheimer’s disease (AD) drug trials for solanezumab and bapineuzumab. Both are monoclonal antibodies that bind beta-amyloid.

With few exceptions, finding drugs to successfully treat AD has been wrought with failure since the middle of the last century. FDA-approved acetylcholinesterase inhibitors, such as Aricept, Razadyne, Cognex, and Exelon, only mask symptoms and do nothing to slow the steady and irreversible decline in brain function.

However, the future holds promise for new drugs with different mechanisms of action, some of which may even slow the disease process itself. They interact with nicotine receptors, secretases, microtubules, calcium channels, trophic factors, and other substances involved in AD.

Based on current clinical trials and reports presented at recent meetings, such as the Society for Neuroscience Convention and the International Conference on Alzheimer’s Disease, mechanisms being investigated that show promise in treating AD include those described below.

Beta-Amyloid Blockers
Beta-amyloid plaques are among the defining diagnostic markers for AD in people with dementia. Their buildup around neurons throughout the brain, especially in the hippocampus, is associated with the disease, even though some people with high levels exhibit no symptoms. Whether they are a cause or an effect remains controversial.

Drugs such as ELND005 (also called Scyllo-inositol) prevent the formation of beta-amyloid oligomers. ELND005 has been shown to inhibit the aggregation of beta-amyloid in transgenic mice, improve many AD-like phenotypes, and protect against cognitive decline.

Microtubule Stabilizers
Microtubules run along axons between cell bodies and axonal terminals and provide the main structure for anterograde and retrograde axonal transport. Normal tau protein is important for stabilizing microtubules inside neurons. When tau is compromised and the tubules become tangled, axonal transport is impaired and neurons die.

Epothilone is a microtubule-stabilizing agent that can cross the blood-brain barrier and compensate for impaired tau function. In research on models of tau disease, epothilone-treated mice performed better on memory tests and maintained healthier and more numerous hippocampal neurons.

Nicotine Receptor Activators
Neurons that release acetylcholine preferentially degenerate in AD. The receptors most affected by this degeneration are the nicotinic alpha 7 receptors. Selective nicotinic alpha 7 receptor agonists, such as RO5313534, restore the stimulation formerly supplied by acetylcholine.

Alpha 7 receptor agonists theoretically can interfere with the neurotoxic effects of beta-amyloid and prevent the cognitive decline of AD patients. RO5313534 has been shown to increase cholinergic transmission in the brain while being safer than current AD drug treatments.

Gamma-Secretase Inhibitors
Beta-amyloid is clipped from its parent compound, amyloid precursor protein (APP), by gamma-secretase. Some researchers believe that drugs that inhibit this enzyme could reduce beta-amyloid accumulation. The problem is that gamma-secretase also is involved in processing another protein, Notch, which has many critical biological functions.

However, imatinib, NIC5-15, and BMS-708163 have been shown to possess gamma-secretase inhibition properties that spare Notch. Imatinib works by inhibiting gamma-secretase activating protein, which promotes gamma-secretase binding to APP but not to Notch. It reduced beta-amyloid production up to 50% both in tissue samples and Alzheimer’s mice while having little effect on Notch processing.

Copper and Zinc Inhibitors
PBT2 focuses on certain metals that help drive the formation of the plaques that distinguish AD from other types of dementia. PBT2 takes copper and zinc away from the amyloid protein so it becomes more difficult to form plaques. A 12-week double-blind, randomized, placebo-controlled trial showed a dose-dependent and significant reduction of cerebrospinal fluid beta-amyloid and significant improvement in executive function with no significant side effects.

According to Rudolph E. Tanzi, PhD, the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School, who helped create the drug, it not only prevents the production of plaques, but also stimulates new neurons to grow in the hippocampus. If the drug proves effective in larger studies, it may be available to people with AD in about five years.

Insulin Enhancers
Insulin resistance and the way brain cells process glucose may be linked to AD. Insulin allows brain cells to access glucose. Brain cells that are resistant to insulin’s effects are deprived of their main source of energy.

Because of decreased exercise and dietary changes, insulin resistance has increased in recent years and, over time, can result in increased inflammation and beta-amyloid accumulation in the brain, which contributes to the risk of AD.

The Study of Nasal Insulin to Fight Forgetfulness involves an investigational treatment using intranasal insulin to increase the uptake of glucose into brain cells. Nasal insulin improves glucose uptake in the hippocampus, which is rich in insulin receptors. Additionally, NIC5-15 is an antidiabetic agent with insulin-sensitizing properties that is being tested as an AD treatment.

Neurotrophic Enhancers
J147 affects several cellular processes associated with AD, including a decreased level of brain-derived neurotrophic factor (BDNF). J147 increases BDNF that protects neurons from toxic insults and helps develop new neurons and synapses.

Developed at the Salk Institute for Biological Studies, J147 reverses memory deficits and slows AD progression in aged mice. The drug was administered in the food of 20-month-old genetically engineered mice with advanced AD. In only three months, J147 increased neurotrophic factors, reduced soluble levels of amyloid, and reversed memory loss.

In another project, J147 was tested against Aricept and was found to perform as well as or better than Aricept in several memory tests.

Calcium Channel Blockers
Impaired regulation of calcium in central neurons is one of the earliest signs of AD. Calcium is regulated by L-type calcium channels, which are required for long-term potentiation in the CA1 region of the hippocampus and thus are essential for long-term memory. Abnormalities in these channels impair memory pathways and eventually cause the death of neurons.

Selective L-type calcium channel blockers protected rat cortical neurons from beta-amyloid–induced calcium influx, suppressed apoptosis, and reduced cell death. The calcium channel blocker MEM 1003 improved learning in aged rabbits tested on eyeblink conditioning tests and may reduce age-related cognitive impairment.

Final Thoughts
Other mechanisms of action of proposed AD drugs include anti-inflammatory drugs and drugs that influence presenilins and ApoE protein, as well as those that enhance glutamate neurons involved in memory. Many proposed AD drugs are pleiotropic, working via numerous mechanisms. The drug development process takes many years and many dollars, but hopefully one or more of these mechanisms will prove beneficial for AD patients.

— Norbert Myslinski, PhD, is a neuroscientist and faculty member in the dental and nursing schools of the University of Maryland in Baltimore and the director of the “Physiology of Aging” course. He founded the Baltimore Chapter of the Society for Neuroscience.

Pathology of Alzheimer’s Disease
The summary below describes the pathology of Alzheimer’s disease (AD). The numbers in parentheses refer to the eight mechanisms of action highlighted in this article and are placed next to the chemical or process they affect. A plus sign indicates stimulation or improvement, and a minus sign indicates inhibition. A- indicates the locus of the common current treatment drugs.

AD initially destroys acetylcholine (Ach) neurons located in the hippocampus involved in the consolidation of memory. Ach activates nicotinic receptors (3+) and then is inactivated by Ach esterase (A-). Trophic factors (7+) enhance the growth and multiplication of these neurons. Insulin (6+) facilitates the cellular uptake of glucose, the neuron’s primary energy source. The definitive AD diagnostic markers for patients with dementia are the buildup of beta-amyloid plaques (1-) around neurons and the entanglement of neurotubules (2-) inside neurons.

Beta-amyloid is synthesized from amyloid precursor protein with the help of secretases (4-) and the metals copper and zinc (5-). Apolipoprotein E plays a critical role in the accumulation and clearance of beta-amyloid. Tau protein is important for maintaining the structure of neurotubules. Inflammation accompanies neuron degeneration in AD.

Calcium channels (8+) on neuronal membranes are important for long-term memory and become impaired in AD. Presenilins also are membrane proteins, mutations of which are associated with familial AD.

— NM

Nonpharmacological Advancements
• In 2012, the FDA approved florbetapir (Amyvid), a radioactive dye used as an imaging agent. Injecting it into patients before a PET scan helps support or rule out an Alzheimer’s disease (AD) diagnosis. The dye binds to beta-amyloid for better visualization and estimation of the amount of plaque present. A negative Amyvid scan indicates few plaques and is inconsistent with an AD diagnosis. A positive scan indicates moderate to high amounts of plaque and increases the likelihood of developing AD but does not establish a definitive diagnosis. FDA approval will generate more clinical and research opportunities for amyloid imaging.

• Cerebrospinal fluid (CSF) production and turnover diminish in AD. Increasing CSF drainage may reduce the accumulation of beta-amyloid, tau, and inflammatory mediators that build up in AD. A new AD treatment features the COGNIShunt System, which uses a shunt similar but not identical to those used to treat hydrocephalus. It is engineered to improve CSF clearance without over drainage. In a year-long study, the dementia rating of the shunt-treated group showed little change compared with a decline in the control group.

• NeuroAD, a treatment being tested at Harvard University, combines noninvasive magnetic stimulation of the brain with cognitive challenges to improve brain circuits’ function. It challenges a person to solve problems on a computer immediately after it uses electromagnetic energy to stimulate the brain region required to give the answer. Treatments last an hour per day and occur daily for six weeks. It improves cognitive abilities for day-to-day tasks such as remembering names and orientation. It already has been approved in some European countries despite the fact that it is expensive, causes mild headaches in some people, and long-term effects beyond three months are not yet known.

— NM