Enzyme Once Thought Harmful To Alzheimer’s Patients Now Appears To Be A Key To Future Treatment

Findings published in current edition of Journal of Neurophysiology

March 12, 2002 -- Bethesda, MD -- The four million Americans who have been diagnosed with Alzheimer’s disease (AD) experience symptoms which include progressive mental deterioration, confusion, a loss of memory and an inability to calculate the simplest of numbers.  This may be due to the fact that people with Alzheimer's have fewer brain cells and less of some important neurotransmitters than people without the disease.

The Importance of Galanin

Previous research has established that a substance called “galanin” is associated with learning and memory and is involved in brain function, and disorders such as epilepsy. When a nerve is cut or injured, the neuron produces extra galanin, possibly to repair or modulate the damage. The production of galanin may be one way that the body tries to repair nerve damage.  Unfortunately, accepted literature states when the onset of AD occurs, galanin hyperinnervation (excessive supply) of nerve cells that employ acetylcholine as their neurotransmitter in the basal forebrain of AD patients occurs and depresses acetylcholine release and its inhibitory actions at other central nervous system sites.

Background

The majority of the scientific community believes this action is detrimental. This is due to a finding that AD wipes out many of the cholinergic neurons of the hippocampus; those that survive in the nucleus show elevated expression of galanin.  However, a new study suggests that by virtue of its excitatory actions on cholinergic neurons, galanin may in fact play a compensatory role by enhancing the release of acetylcholine from remaining cholinergic basal forebrain neurons. This action might serve to delay the progression of Alzheimer's disease linked to a reduction in central cholinergic tone.  This raises the possibility that induction of galanin by nerve growth factor may have a neuroprotective role.

The Study

To examine this theory, an investigation of the mechanism of action of this peptide was undertaken in the cholinergic basal forebrain. A team of researchers investigated the actions of galanin on acutely dissociated rat cholinergic basal forebrain neurons from the nucleus of the diagonal band of Broca (DBB) using a combination of whole cell patch-clamp and single-cell reverse transcription-polymerase chain reaction (RT-PCR) analysis.

The authors of "Novel Excitatory Actions of Galanin on Rat Cholinergic Basal Forebrain Neurons: Implications for Its Role in Alzheimer's Disease," are Jack H. Jhamandas, Kim H. Harris, David MacTavish, and Balvinder S. Jassar, all from the Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.  Their findings appear in the current edition of The American Physiological Society’s Journal of Neurophysiology.

Methodology 

Brains were quickly removed from decapitated male rats and placed in cold artificial cerebrospinal fluid that contained a mixed solution. Brain slices were cut and the area containing the DBB was dissected out. Although most of the tissue contained the horizontal limb of the DBB, some slices may have included a component of the vertical limb of the DBB.

Acutely dissociated neurons were prepared by enzymatic treatment of slice with trypsin, followed by mechanical conversion to a fine powder for dispersion of individual cells. Cells were then plated on poly-L-lysine-coated cover slips and viewed under an inverted microscope. All solutions were kept oxygenated by continuous bubbling with pure oxygen.

Results

The findings provide the first electrophysiological evidence that the neuropeptide galanin causes a response from central neurons found in mammals. Activation of galanin receptors results in membrane depolarization and an increase in excitability of basal forebrain neurons, which is related in part, through its effects in reducing specific voltage- and calcium-dependent potassium conductances. Furthermore, these actions of galanin are specific to cholinergic and not GABAergic.

Conclusion

On the basis of galanin-induced inhibition of ACh release, it has been hypothesized that the increased galanin innervation of cholinergic neurons might play an important role in worsening cognitive function of Alzheimer's disease patients.

An Alternate Theory

The research findings from this Canadian study suggest another alternative to that theory. Galanin overexpression in Alzheimer's disease may serve a compensatory role by enhancing the release of ACh from the remaining cholinergic basal forebrain neurons. This notion is supported by the observation that nerve growth factor, which rescues degenerating cholinergic neurons and increases ACh turnover by upregulating  ChAT synthesis also induces galanin gene expression in the cholinergic basal forebrain. This recommends that an increase in galanin, through its excitatory effects on the cholinergic basal forebrain neurons, could cause increased release of ACh, which would be entirely consistent with the effects of nerve growth factor on cholinergic function.

An important consequence of the findings presented here relates to the development of galanin antagonists, which have been promoted as a possible treatment option for AD. Our findings should inject a note of caution in viewing such antagonists as "neuroprotective," a notion that is based on their potential to reverse the inhibitory effects of galanin, which may be receptor and region specific in the central nervous system.

Source: February edition of the Journal of Neurophysiology  

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The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

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Editor’s Note: To set up an interview with a member of the research team, please contact Donna Krupa at 703.527.7357 (direct dial), 703.967.2751 (cell) or djkrupa1@aol.com.