By actively affecting how the brain learns and functions,

Galantamine Protects White Matter
In an Alzheimer’s disease animal model

By Will Block

W


Figure 1. cortical. (Anything to do with the cerebrum is called cerebral and anything to with the cerebellum is called cerebellar.) White matter lying close to the cortex is called subcortical (or superficial). White matter lying deeper into the brain is called deep white matter.
hite matter (WM) integrity is critical in neural conduction between brain regions and cognitive performance. WM is comprised mostly of myelinated axons. Myelin is a fatty white substance that surrounds the axon of nerve cells, forming an electrically insulating layer. [See Fig. 1 below, and “Ketones and White Matter” on page 5.]

White Matter Lesions

Growing interest in aging continues to attract attention to WM lesions in Alzheimer’s disease (AD). In a new study,1 researchers investigated the roll of cerebral hypoperfusion (HP) in APP23 AD mice. HP is the reduction of blood flow to all parts of the brain, resulting in inadequate supply of oxygen and nutrients to the body tissues, with serious health consequences.

The researchers then investigated the altered key protein molecules in the nodal, paranodal, and intermodal sites in the white matter, as well as the efficacy of galantamine (see Fig. 2).


Disruption of such architecture of
myelinated axons could impede
neuronal conduction and finally lead
to a decline in cognitive function.

Such abnormal neuropathological
processes were normalized with
galantamine treatment.


Cerebral HP was induced in APP23 mice to mimic AD. However, when compared with wild type mice and simple APP23 mice, APP23 + HP mice showed a progressive loss of myelin-associated glycoprotein (MAG) beyond the primary nodal region in the corpus callosum.

Figure 2 Schematic illustration of key protein molecules at nodes of Ranvier, paranode and internode of corpus callosum in normal (WT, i), APP23 (ii), APP23 + HP (iii), and APP23 + HP + galantamine treatment (iv) mice.

Note the small loss of nodal anchor NF186 in APP23 (ii), which was exaggerated in APP23 + HP mice with MAG/MBP disruption at the internode/paranode and extension of Nav1.6/AnkG from the original nodal site to the paranodal site (iii). Galantamine treatment ameliorated such pathological processes (iv).

LEM1605Figure2_274.jpg;
(click on thumbnail for full sized image)

WM Disruption Prevented by Galantamine

On myelinated fibers, the nodes of Ranvier (myelin sheath gaps) are flanked by paranodes (axon-glial junctions) and internodes (juxtaparanodal regions), which are characterized by specific protein complexes (see Fig. 2).

The molecular components of the nodes possess voltage gates and myelin-associated glycoproteins (MAG), which are critical for axon-glia junctions, and those of the internode are MAG and myelin basic protein (MBP), which are localized on glial cells (Fig. 2i). Disruption of such architecture of myelinated axons could impede neuronal conduction and finally lead to a decline in cognitive function.

Such abnormal neuropathological processes were normalized with galantamine treatment. Galantamine, which is currently used for treatment of AD, inhibits acetylcholinesterase, modulates nicotinic acetylcholine receptors (nAChRs), and exerts anti-oxidative and anti-inflammatory effects. The present study demonstrated that cerebral HP strongly disrupted WM integrity at internodal, paranodal, and Ranvier’s nodal sites, which are associated with cognitive decline. Galantamine treatment significantly protected such WM integrity by allosterically potentiating ligand action. In biochemistry, allosteric potentiation is the instruction of a protein to bind an effector molecule at a site other than the enzyme’s active site.


Galantamine treatment significantly
protected WM integrity by
allosterically potentiating ligand
action. This further suggests the
potential antiinflammatory effect of
galantamine.


Other reports demonstrated that galantamine improved spatial working memory and significantly rescued WM ligands by suppressing microglial activation through allosterically potentiating ligand action. This further suggests the potential anti-inflammatory effect of galantamine. In the present study, WM was significantly rescued by galantamine treatment, probably by an anti-inflammatory effect (Fig. 2iv).

Reference

  1. Zhai Y, Yamashita T, Nakano Y, Sun Z, Morihara R, Fukui Y, Ohta Y, Hishikawa N, Abe K. Disruption of white matter integrity by chronic cerebral hypoperfusion in an Alzheimer's disease mouse model. J Alzheimer’s Dis. 2016 Apr 12. [Epub ahead of print] PubMed PMID: 27079724.

For Dr. Ward Dean’s article on “White Matter Disease,” see his response in “Health Matters” in the October, 2015 issue (http://www.life-enhancement.com/ magazine/article/3444-white-matter-disease). At the end, he writes, “Cholinesterase-inhibiting substances such as galantamine may help with [the type of] cognitive disorders [discussed].


Will Block is the publisher and editorial director of Life Enhancement magazine.

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