Connection Between BSE And Alzheimer's?

Mad Cow Disease and Alzheimer's — Is there a connection?

Biochemist Colm Kelleher speculates that the infectious "prion" proteins that cause Mad Cow Disease and its brain-wasting human variant, Creutzfeldt-Jakob Disease (CJD), could be a factor in the substantial increase in cases of Alzheimer's disease in recent years. His book Brain Trust (2006) is a medical detective story that traces the origin and spread of the deadly infectious prions that cause Mad Cow disease as they jumped species and ended up in America's food supply. It also shows how human Mad Cow disease is hidden in the current epidemic of Alzheimer's Disease. However according to the " BSE ammonia- magnesium theory " (http://www.bse-expert.cz) there can be a "no infectious connection" ; see following "BSE and Alzheimer's relationships" about this theory;1. The origin of BSE according to the alternative „ammonia- magnesium theory“

There is the possibility that hyperammonemia plus hypomagnesaemia „simultaneous“ action have a strong influence on the CNS, especially in ruminants (Mg absorption in the rumen, especially), so that the BSE has its roots in a more common nutritional problem. This alternative „ ammonia- magnesium theory“ is based on the chronic Mg-deficiency potentiated by hyperammonemia in ruminants. As a typical example; the ryegrass staggers is showed in ruminants. So, various clinical symptoms can be observed because the nervous system controlling both voluntary and unvoluntary muscles is affected (Mg and Ca disturbances).

It seems, that during the chronic hypomagnesemic disease, the heavy weather changes (cold- rainy, windy...) or nutrition (high intake of crude protein...) stress - these episodes of acute abruptions, may accelerate the nervous, like to „BSE“ disease. If the BSE is involved; a longer- chronic action of corresponding biochemical changes in the blood (CSF) is necessary, to rise irreversible neurodegenerative changes. Early of prion diseases, neurons develop intracytoplasmic vacuoles. As the disease progresses, vacuolization becomes more pronounced and advanced cases show neuron loss, gliosis (astrocytosis), and brain atrophy.

Cellular prion protein (PrPC) is associated with regulation of intracellular free calcium levels through an interaction with voltage-sensitive calcium channels. Toxic effects displayed by PrPSc (scrapie prion protein) can be blocked by antagonists of N-methyl-D -aspartate (NMDA) receptor channels.

An important consequence of NMDA receptor activation is the influx of Ca2+ into neurons. Overstimulation of the NMDA receptor as well as other excitatory amino acid receptors results in neurotoxicity and neuronal injury. These receptors are considered as the final common pathway for many acute and chronic neurologic conditions.

Studies have demonstrated that Mg2+ can protect against NMDA- induced neurodegeneration, brain injury, and convulsions. Mg2+ competes with calcium at voltage- gated calcium channels both intracellularly and on the cell surface membrane. Mg2+ is capable of blocking NMDA receptors both intracellularly and extracellularly.

While non-ruminants absorb Mg primarily from the small intestine, ruminants are able to absorb much of their Mg requirement from the rumen. As the dietary protein is readily fermentable, it leads to increased intraruminal ammonia and is normally dotoxified in the liver to urea. However, a high rate and extent of degradation of crude protein causing high concentrations of ammonia – N in rumen results in hyperammonemia, (because of diminished capacity of liver to synthetise urea in ornithine cycle), and ruminal ammonia contribute to decreased Mg absorption. It seems to me that there is the begining about the „BSE vicious circle“ (see Fig.1). So, I described a Czech alternative „ammonia- magnesium“ BSE theory (Bulletin of Research Institute of Cattle Breeding in Rapotín , Czech Republic; March, 2001), see also this text „reprinted“ to international journal „Feed-Mix“ (June, 2002) (http://www.agriworld.nl/feedmix/headlines.asp?issue=3).

a/ Action of the hyperammonemia

Ammonia is a main factor in the pathogenesis of hepatic encephalopathy (HE), the CNS is most sensitive to the toxic effects of ammonia. Acute ammonia toxicity is mediated by activation of NMDA receptors. In this process of neuronal death is known that the rise of intracellular Ca2+ is an essential step. A rapid increase in ammonia- acute exposure to ammonia; results in an increase in pHi (intracellular alkanization) in all cell types, including astrocytes. This results in cytosolic alkalinization (pH action) and leads to calcium-dependent glutamate release from astrocytes. Intracellular alkalinization is accompanied with an increase in (Ca2+)i in neurons.

During ammonia intoxication, NMDA receptors are excessively stimulated, resulting in a larger influx of Ca2+ than usual into neurons. This would elicit a cascade of reactions and eventually lead to neuronal cell death. It has been shown that NH4+ induced depolarization in cultured rat cortical astrocytes . This ammonia-induced depolarization could also take place in neuronal membranes and result in removal of Mg2+ that normally blocks the NMDA receptor channel, leading to excessive activation of the NMDA receptor.

So, the effects of ammonia may be responsible for the reduced astrocytic uptake of neuronally-released glutamate and high extracellular glutamate levels consistently seen in experimental models of the hepatic encephalopathy (HE).

b/ Action of the Mg- deficit

Under normal conditions of synaptic transmission, the NMDA receptor channel is blocked by Mg2+ sitting in the channel and only activated for brief periods of time. Under pathological conditions, however, overactivation of the NMDA receptor causes an excessive amount of Ca2+ influx into the nerve cell, which then triggers a variety of processes that can lead to necrosis or apoptosis.. For example energetically compromised neurons become depolarized because in the absence of energy they cannot maintain ionic homeostasis; this depolarization relieves the normal Mg2+ block of NMDA receptor-coupled channels because the relatively positive charge in the cell repels positively-charged Mg2+ from the channel pore. Hence, during periods of ischemia and in many neurodegenerative diseases, excessive stimulation of glutamate receptors is thought to occur.

Elevations in extracellular glutamate are not necessary to invoke an excitotoxic mechanism. Excitotoxicity can come into play even with normal levels of glutamate if NMDA receptor activity is increased, e.g., when neurons are injured and thus become depolarized (more positively charged); this condition relieves the normal block of the ion channel by Mg2+ and thus abnormally increases NMDA receptor activity.

Astrocytes in the brain form an intimately associated network with neurons. They respond to neuronal activity and synaptically released glutamate by raising intracellular calcium concentration Ca2+. Ability of most neurotransmitters to increase astrocytic Ca2+ levels is firmly established. Astrocytes regulate neuronal calcium levels through the calcium-dependent release of glutamate. Astrocytic glutamate release pathway is engaged at physiological levels of internal calcium. Astrocytic glutamate release can be triggered by any ligand that stimulates an increase in Ca2+...


2. Overstimulation of the NMDA receptor; the connection between Mad Cow Disease and Alzheimer's?

Glutamate mediates most fast excitatory synaptic transmission in the central nervous system, by activating three subclasses of ionotropic receptors--amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, and N-methyl-D-aspartate (NMDA). Glutamate receptor activation is necessary for normal sensorimotor control, as well as synaptogenesis and synaptic plasticity , but excessive activity of these receptors can contribute to neuronal death in a variety of neuropathological processes, including ischemia, seizures, and neurodegenerative diseases such as amyotrophic lateral sclerosis, Parkinson disease and Huntington disease (DiFIGLIA 1990; KOCHLAR et al. 1988; PARK et al. 1988; ROTHSTEIN et al. 1990, 1992; SIMON et al. 1984; SRIVASTAVA et al. 1993; TURSKI et al. 1991). The NMDA-type glutamate receptor is thought to play the critical role in induction of synaptic plasticity as well as cell death because of its voltage-dependent magnesium block, high calcium permeability, and slow deactivation and desensitization (BLISS and COLLINGRIDGE 1993; DINGLEDINE et al. 1999).

Overstimulation of the NMDA receptor by glutamate is implicated in neurodegenerative disorders. Accordingly, REISBERG et al. (2003) investigated memantine, an NMDA antagonist, for the treatment of Alzheimer's disease. Antiglutamatergic treatment reduced clinical deterioration in moderate-to-severe Alzheimer's disease, a phase associated with distress for patients and burden on caregivers, for which other treatments are not available.

Persistent activation of NMDA receptor in the central nervous system has been considered to contribute to chronic neurodegeneration in Alzheimer's disease. Memantine is postulated to exert its therapeutic effect through its action as a moderate-affinity, uncompetitive NMDA receptor antagonist (LIPTON, 2006). The Cholinergic system is a system of nerve cells that uses acetylcholine as its neurotransmitter, it is damaged in the brains of people with Alzheimer's.

Conclusion

According to the BSE ammonia- magnesium theory , there the origin of BSE is a long-term high protein intake with the coincidence of dietary magnesium -deficiency. It seems that the same can be about the Alzheimer's disease.

Read the news article that this opinion was posted about:
Alzheimer's Protein Shredded By Enzyme

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