Alzheimer's disease, oxidative injury, and cytokines

William K. Summers, MD
Alzheimers Corporation,
Albuquerque, NM, USA

Helen A. Korneva, M.D.
Institute for Experimental Medicine,
St. Petersburg, Russia

Synonyms: Alzheimer's disease, Senile dementia of the Alzheimer's type, Senile dementia.

Definitions:

Alzheimer's disease: a progressive dementing illness, typically fatal within eight to ten years due to intercurrent infections such as pneumonia. At autopsy there is generalized shrinking of the brain. Microscopically the hallmarks are ß- amyloid laden plaques and tau protein laden tangles. Current belief is that the disease is caused by toxicity from ß -amyloid or tau protein.
Oxidative injury: see below
Cytokines: see below

Characteristics:

ALZHEIMER'S is not caused by ß- amyloid:

Tomb stones do not kill, unless they fall upon the living. Tomb stones mark where the dead reside. To discover the cause of death, the body needs to be exhumed and analyzed. Even then, the cause of death may not be discovered.

For three decades, scientists pursued plaques (ß amyloid) and tangles (tau protein) as causal Alzheimer's disease (AD)[1]. It is not the first time science went in a wrong direction. Plaques and tangles are tombstones. But, evidence has been show that ß amyloid and tau protein are toxic to neurons [1,2]. Yes. But this is similar to dropping tomb stones on the living.

What, then, causes AD? When does it start?

A logical hypothesis with substantial support is that various CNS insults initiate oxidative injury with a pathologic immune response resulting in smoldering CNS microlocalized inflammation (mLI)[2]. The MIs create plaques and tangles. Over two or more decades these pockets of inflammation metastasizes to other areas of the brain. Pre-clinically this is called mild cognitive impairment (MCI). As time passes, this becomes Alzheimer's which leads down the familiar path to death.

What are the initiating brain insults? The general classes would be mechanical trauma (sports, auto accidents); infections (herpes simplex viruses, cytomegalovirus, HIV, chlamydia pneumoniae, syphilis); anoxia (stroke, cardiac arrest, hemodynamic shock, pulmonary emboli, sleep apnea syndrome); metabolic (diabetes, B12 deficiency, hypothyroidism, obesity, hypertension, homocysteinaemia); and toxic (iron, mercury, bismuth) [2,3]. The list of CNS insults that are related to AD is growing.

The Role of Excitotoxin Neurotransmitters and the Release of Free Radicals:

The CNS insult must result in focal neuron death by either necrosis or secondary apoptotic damage. This results in massive release of the excitatory amino acid, glutamate into the extraneuronal space [3]. L-glutamate, the most abundant excitatory neurotransmitter, binds to AMPA and NMDA receptors to precipitate localized neuronal apoptosis. This is accomplished by Na+ ion influx with acute osmotic damage followed by apoptosis. Or it is accomplished by Ca++ influx and delayed apoptosis. Both necrosis and apoptosis release free radicals (ROS/RNS) into the intracellular space. Indeed L-glutamate is a neurotransmitter free radical. However, release of mitochondrial contents injects metals (copper, zinc, iron, etc) into the intracellular space. Homeostasis is threatened. This is where nitric oxide (NO), anti-oxidants, Beta amyloid and cytokines come into play.

NO is a free radical, but is part of homeostasis [3]. Rapidly formed, it interacts with superoxide radicals (02$-) to form more innocuous products which antioxidant mechanisms can manage.

Oxidative Injury:

Metabolism produces reactive oxygen species (ROS) and reactive nitrogen species (RNS) which is approximately balance by antioxidant defense systems of the body. Anoxia, blunt trauma, infections, and any cause of inflammations creates an excess of ROS/RNS. Serious imbalance between production of ROS/RNS and the antioxidant defense results in oxidative injury or disruption of DNA, proteins (enzymes), and lipids.

The brain is uniquely vulnerable to oxidative injury [2]. In the milieu of local necrosis / apoptosis the free radicals test the ability of the brain to protect lipid membranes. 50-80% of neurons by weight are lipids. The brain has antioxidant methods to protect the neuronal membrane [2,4]. As these local defenses fail, markers of oxidative damage should be evident. Indeed activated NF?B, 8-OHdG, protein carbonyls, nitrotyrosine, 4-HNE, and other markers of oxidative injury are elevated in AD. Further these markers are associated with senile plaques and paired helical filaments [4].

Cytokines:

Concomitant with and as the mLI persists, cytokines come into play. Cytokines are low molecular weight regulatory proteins secreted by cells to orchestrate host immune processes [2,5]. They regulate proliferation, maturation, enhanced inflammation or dampened inflammation. Important properties of cytokines are: i]pleiotropy (one cytokine has multiple targets and multiple actions) ii]redundancy (several different cytokines have similar actions) iii]countervailing actions (one cytokine may stimulate or inhibit production of others) iv]cytokines precipitate or truncate cascades of other cytokines v]cytokines increase or decrease receptor sensitivity for other cytokines or even themselves vi]CNS cytokines stimulate or inhibit both local cytokine response and distant (non-CNS) cytokine response.

Only recently has it been recognized that cytokines are produced by all four major CNS cell groups. These are neurons, oligodendrocytes, astrocytes, and microglia. Over two hundred distinct cytokines identified to date are divided into three groups and 12 sub groups (families) [2,5] Chemokines are a subgroup of 50 small cytokines that are central to mediation of inflammatory responses. Most of these are produced by CNS cells [6]. Some cytokines tend to be proinflammatory and promote apoptosis. Example are TNF-α, IFN-γ, IL1ß, IL-6, IL-8, IL-18, MCP-1, MIP-1?, MIP-1ß, IP-10, and RANTES. Some CNS cytokines tend to down regulate inflammation and promote growth/ repair. These would include BDNF, ß-NGF, GDNF, G-CSF IL-1ß, IL-4, IL-10, IL-13, and NT-3, 4/6, 6. This list changes near daily. Further one cytokine may be found to be proinflammatory in one region or circumstance, and have an opposite effect under other circumstances. CNS cytokines may stimulate distant response. For example, blood levels of IL-2 correlate with severity of Alzheimer's disease. External application of cytokines can induce CNS patterned responses. For example, administration of IL-2 will induce depressive symptoms.

Sustained elevations of cytokine productions are associated with pathologies. In the case of AD, the key cytokines are IL-1 which induces iNOS expression by astrocytes and then potentiates NMDA - glutamate neurotoxicity [7]. IL-1 may also be neuroprotective. Interleukin-6, produced by neurons, astrocytes and microglia co-localizes with Aß plaques. Peripherally, IL-6 is a marker of chronic inflammation. Elevated IL-6 is seen in chronic simple anemia, rheumatoid arthritis, Crohn's disease and others [5]. Il-6 is involved in protecting neurons from methylmercury [7]. It is probably involved with Aß neuroprotection by neutralizing metalloproteins ROS/RNS produced by apoptosis [2,8]. TNF-alpha typically is a harbinger that calls forth other inflammatory cytokines. In AD there is mixed evidence at the present time. Macrophage Colony Stimulating Factor (MCSF, CSF-1) appears to be involved with upregulated cytokine / iNOS response to Aß [7]. A growing list of chemokines is involved with AD. Transforming Growth Factor (TGF-ß) cytokine family, which includes the neurotrophin subfamily, are expressed by neurons, astrocytes, and microglia. The neurotrophin subfamily include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), insulin like growth factor (ILGF), glial derived neurotrophic factor (GDNF), and erythropoietin (EPO) [2,5,9] These stimulate repair, growth, and neurogenesis [2,10].

What is the role of Aß in Alzheimer's disease?

Perry, Smith, et al offer a logical explanation [2,8] Aß is actually part of the brain's efforts to maintain homeostasis. Apoptosis and necrosis resulting from mLI cause release of mitochondrial metalloproteins and metals (iron, zinc, copper, etc) into an acidic extracellular matrix. Aß is induced by cytokines. Aß binds copper, zinc, iron and others. Aß absorbs these ROS/RNS as part of homeostasis. Adequate circulation should allow clearance of the Aß -metal complexes. When the microglia are activated, and when the ROS/RNS are overwhelming, myeloid-specific enzyme myeloperoxidases (MPO) consume them to produce MPO-H2O2. This MPO-H2O2 creates cross linkage with Aß protein to precipitate it into insoluble plaques [2].

With plaque formation, activated microglia, highly reactive ROS (including glutamate) the table is set for distant penumbra effect. The mLI can trigger distant microinflammations by transaxonalBtranssynaptic flow, intracellular flow, and vascular dispersion of ROS/RNS. So plaques and tangles develop elsewhere in the CNS, and after decades the victim dies of AD.

What interventions are possible in Alzheimer's disease?

Use of cytokines, anti-cytokines, cytokine receptor modulators is not a current therapeutic intervention. The pleiotropy, redundancy, and unexplored effects of cytokine cascades would result in unanticipated adverse side effects [2,5] Down modulating the effects of glutamate is both practical and available. NMDA antagonists memantine and amantadine are available, and by personal experience of the authors effective early in the course of AD [7]. Third, are anti-inflammatory medications. These have been disappointing to date, possibly due to the drawbacks noted for cytokines [1]. Vaccinations against Aß are fraught with problems, as one is developing immunity against a homeostatic mechanism. Finally there are antioxidants. Inexpensive vitaminers and herbals are available and have increasing scientific support [2,4,11]. Traditional medicine discounts these, while pursing patentable pharmaceuticals. Further research on synergistic combinations of antioxidants may prove effective.

Because the authors were limited to ten references, the choice was made to cite recent books with a larger number of specific references.

References

1. Behl C (2002). Neuroprotective strategies in Alzheimer's disease. IN: Alzheimer C (ed) Molecular and Cellular Biology of neuroprotection in the CNS. Kluwer Academic/Plenum Publishers, New York, p 475-496.
2. Summers, WK (2004). Alzheimer's disease, oxidative injury, and cytokines. J Alz Dis. 6:651-657.
3. Gillessen T, Budd SL, Lipton SA (2002). Excitatory amino acid neurotoxicity. IN: Alzheimer C (ed) Molecular and Cellular Biology of neuroprotection in the CNS. Kluwer Academic/Plenum Publishers, New York, p 3-40.
4. Halliwell B and Gutteridge JMC (2001). Free Radicals in Biology and Medicine (3rd ed). Oxford University Press, Oxford, p 617-859.
5. Vilcek J (2006). Cytokines: Wherefrom and Whereto. IN: Ransohoff RM, Benveniste EN (eds) Cytokines and the CNS. Taylor & Francis, New York, p 23- 37.
6. Dey N, Durden DL, Van Meir EG. Cytokine expression and signaling in brain tumors. N: Ransohoff RM, Benveniste EN (eds). Cytokines and the CNS. Taylor & Francis, New York, p 194-228.
7. Murphy GM, Saravanapavan P (2006). Cytokines and neurodegeneration. IN: Ransohoff RM, Benveniste EN (eds). Cytokines and the CNS. Taylor & Francis, New York, p163-191.
8. Castellani RJ, Lee H, Perry G, Smith MA (2006). Antioxidant protection and neurodegenerative disease: The role of amyloid-ß and tau. Am J Alz Dis Oth
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9. Dechant G, Neumann H. Neurotrophins (2002). IN: Alzheimer C (ed) Molecular and Cellular Biology of neuroprotection in the CNS. Kluwer Academic/Plenum Publishers, New York, p 303-334.
10. Unsicker K, Krieglstein K (2002). TGF-ßs and their roles in the regulation of neuron survival. IN: Alzheimer C (ed) Molecular and Cellular Biology of neuroprotection in the CNS. Kluwer Academic/Plenum Publishers, New York, p 353-374.
11. Packer L, Ong CN, Halliwell (eds)(2004). Herbal and Traditional Medicine. Marcel Dekker, New York.