Alzheimer’s and Epilepsy

Identifying “silent seizures” in Alzheimer’s patients and seeking novel ways to use anti-seizure
medications

2009 Seed Grant
Dean M. Hartley, Ph.D.
Rush University

Alzheimer’s disease (AD) is an irreversible, progressive brain disorder. AD destroys neurons,
causing memory loss, confusion and impaired judgment. It is characterized by the formation of
two pathological features, plaques and tangles. Plaques are made from a fragment of the
protein called beta-amyloid and buildup between the neurons. Tangles form inside neurons and
consist of twisted bundles of fibers of a protein called tau.

Research has shown that over time, these two abnormal pathologies spread through the brain
in a very characteristic pattern and the Hartley lab is particularly interested in the progression of
the plaques. In the earliest stages, plaques are only present in the upper areas of the brain.
However, as the disease progresses the plaques moves to other specific areas lower in the
brain, as though they are following specific pathways. These cues suggest that the disease is
moving by electrical activity through specific neuronal pathways, connecting one area to the
next, driving new pathology. Understanding how this progression occurs is key in
understanding how to stop this disease.

Dr. Hartley is using his 2009 BRF Seed Grant to examine the possible role of seizure-like
activity in the progression of AD. Dr. Hartley’s working model is that brain cells become
“hyperactive,” similar to the activity measured during very mild seizures; this abnormal activity
then causes the characteristic AD pathology to develop in this area. Moreover, this hyperactivity
travels to other regions by specific connections causing a cascade of hyperexcitability and
subsequent AD pathology; this specific hyperactivity drives the progressive pathology in the
brain.

Studies have reported seizure-like activity in AD patients and animal models of AD. Recent
studies in animal models of AD have shown a type of “silent seizure,” suggesting there is an
undetected hyperactivity in the AD brain. Dr. Hartley is testing his hypothesis by placing
sensitive monitoring devices in a mouse model of AD to determine if the sequence of the
developing pathology is preceded by hyperactivity.

To further understand this problem, drugs that block this hyperactivity, including anti-seizure
medications, will be administered at different time periods. This will help in understanding if
hyperactivity is involved, and also determine if interrupting hyperactivity at a specific time may
block “downstream” areas from developing AD pathology. A better understanding of this
relationship is warranted and may be extremely valuable in identifying mechanisms responsible
for this devastating disease. Most importantly, this understanding may suggest that drugs
blocking or reducing hyperactivity in the brain may be able to stop the initiation or progression of
the disease; currently we are only able to treat the symptoms. The potential of this research is that antiepileptic drugs, which block neuronal hyperexcitability, may be useful in treating AD. Because these drugs are currently used to treat epilepsy, they could be rapidly transitioned to
the treatment of AD.

New research suggests that a healthy diet, exercise and social interaction can reduce the risk of
cognitive decline and AD.

Up to 5.1 million Americans are living with AD (NIH AD Fact Sheet). As the U.S population
ages, this number will significantly increase unless a treatment or cure can be found.

Other Grants

Lindsay M. De Biase, Ph.D., University of California Los Angeles
The role of microglial lysosomes in selective neuronal vulnerability
Synapses, the sites of signaling between neurons in the brain, play essential roles in learning, memory, and the health of neurons themselves. An enduring mystery is why some neurons are…
How the nervous system constructs internal models of the external world
As animals navigate their environments, they construct internal models of the external sensory world and use these models to guide their behavior. This ability to incorporate ongoing sensory stimuli into…
Xiaojing Gao, Ph.D., Stanford University
When Neural Circuits Meet Molecular Circuits: Quantitative Genetic Manipulation with Single-cell Consistency
Cells are the building blocks of our bodies. We get sick when the cells “misbehave”. The way modern gene therapies work is to introduce genes, fragments of DNA molecules that…
Rafiq Huda, Ph.D., Rutgers University
Conducting the orchestra of movement—functional role of striatal astrocytes in health and disease
Movement requires coordinated activity across a large brain-wide network. The striatum is a particularly important part of this circuit; it integrates motor-related information from many distinct brain regions to regulate…