Dementia - The Autophagic model

The autophagic model of Alzheimer’s Disease

Examination of the processes that occur during the progressive destruction of the brain seen during the development of Alzheimer’s disease, could lead one to the generation of an Autophagic model of the disease. Autophagia (aw-t-uh-fe-jee-uh), is normally restricted to a process in which damaged organelles with the cell are slowly digested. There is, though, another type of autophagia in which bodily nutrition is maintained by sacrificial breakdown of some bodily tissues. Such a process could well be used to describe the series of events that occur in the brain, thereby resulting in the development of the characteristic morphology of the brain observed in AD.

In this model, in the prodromic phase of AD, the metabolism of glucose in the brain is affected, as would happen by a deficiency in vitamin B1, and/or vitamin B2. The result is that the favoured energy source of the brain, glucose is compromised, leading to lower energy production within the nerves of the brain and hence lower "processing speed".

1. Simple vitamin deficiency. Deficiency (ies) in vitamin B1 and/or vitamin B2 would result in reduced activity of the enzymes pyruvate dehydrogenase and also alpha-ketoglurate dehydrogenase (1,2,3). Altered glucose metabolism in AD is fairly well documented (4,5,6,7,8) , however, the cause of the altered metabolism is generally over-looked by most, with few citing B1 or B2 deficiency as being causal (1,2,3). Lack of activity of pyruvate dehydrogenase results in elevation of lactic acid (in straight B2 deficiency) and an elevation in pyruvate (in B1 deficiency), representing energy lost in glycolysis and increased excretion of these products which would later result in an increase of these easily assayable markers in urine.

2. Reduced Acetylcholine Production. A consequence of reduced activity of pyruvate dehydrogenase in the brain, is that pyruvate is not converted to acetyl-CoA, and so levels of acetyl CoA would be reduced, which would in turn reduce the production of acetyl-choline in the brain (also known to occur in AD). Lack of acetyl-choline in turn would lead to lack of production of acetyl-choline, and lack of acetyl-choline is linked to loss of cholinergic neurons, and subsequent memory and attention deficits, a feature of AD (9,10,11).

Apart from glycolysis, potentially, acetyl-CoA can be obtained from metabolism of fat, however this is not the preferred energy source in the brain and additionally, as in functional B2 deficiency you can’t burn fat for energy as each of the enzymes involved in fatty acid metabolism is dependent upon the active form of vitamin B2 (FAD), for its activity..

There is a third way to generate acetylcholine, and that is via the metabolism of glucogenic amino acids (but this is blocked due to lack of activity of pyruvate dehydrogenase), or via metabolism of the ketogenic amino acids, Leu, Lys, Phe, Trp, Tyr and Ile. Of these Leucine and Isoleucine (2 of the 9 essential amino acids) are branched chain amino acids. The metabolism of branched chain amino acids, however, requires the adenosylcobalamin-dependent enzyme, methylmalonyl-CoA mutase.  In functional B2 deficiency the lack of activity of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) (both FAD/NAD(P)H dependent) means that one eventually (or the AD person specifically) becomes vitamin B12 deficient, and B12 deficiency is also known as a co-factor in dementia/AD (12-24). Potentially though it would be possible to still generate a small amount of acetyl-CoA from the other ketogenic amino acids, Lys/Phe/Trp and Tyr, and of these Phe, Trp and Tyr are all required to make neurotransmitters, dopamine, epinephrine, nor-epinephrine, serotonin and melatonin. Theoretically you could also still sacrifice the production of these neurotransmitter for energy production, but in methyl B12 deficiency and in iron deficiency (also common in AD), the activity of the critical Kreb cycle enzyme, aconitase is reduced as there is reduced synthesis of the iron-sulphur complex, and reduced aconitase activity has also been shown to be a feature of AD, with mini-mental score estimations paralleling the activity of aconitase (26).

3. Breakdown of the Myelin Sheath. At this stage you have a brain desperate for energy and so it starts to “look” for new energy sources, and as it sits in a sea of fat, the lipids in the myelin sheath, and the accompanying myelin basic protein (MBP) it potentially could gain energy from either source. The brain “may know” that it can’t metabolize fat, but it should still be able to get energy from the MBP in the myelin sheath. So starts the loss of myelin in the brain, which also is typical of AD. This then would correlate with the autophagic stage of AD, hence the tag (27). Alterations in Tau, appear to post-date the decline in myelin sheath thickness.

In the autophagic stage, it is proposed that the brain tries to obtain energy from the break-down of the myelin sheath and the possible use of glycerol released from triglycerides, and the break-down of myelin basic protein to provide ketogenic and glucogenic amino acids for energy. Workers such as Klosinski and co-workers (28) have postulated that myelin is a potential ketogenic fuel supply for the brain, but in the absence of functional vitamin B2, the observed increase in short chain fatty acids, may more represent unmetabolized fats released due the break-down of the myelin sheath. As the autophagic state progresses there is a progressive loss of myelin thickness in the brain, which presumably accounts for the brain shrinkage seen in B12 deficiency and in the development of AD.

4. Weight Loss. Autophagia is not restricted to the break-down of myelin in the brain, and weight loss, frailty and cognitive decline are typical in the progression of dementia to AD (29-34). Not surprisingly, the rapidity of weight loss correlates with both cognitive decline and the reduced survival time (34, 35)). What is surprising is that individuals studying this phenomenon have failed to associate brain shrinkage, loss of myelin sheath and reduced energy output from mitochondria with paralleled frailty and weight loss.

5. Reduction in Vitamin B12 levels in the Brain. Accompanying the lack of vitamin B2 with the subsequent loss of functional vitamin B12, there is a reduction in the synthesis of melatonin (36) and adrenalin, which is inversely correlated with an increase in the neurotransmitter metabolites, HVA/VMA/QA and KA (37,38,39). Quinolinic acid (QA) is known to be neurotoxic and elevated QA have been associated with neurocognitive disorders, schizophrenia and depressive disorders (40). Elevated HVA has been implicated in neuronal toxicity and has been associated with motor impairment in Parkinson’s disease (41), and aggressive behaviour in frontotemporal dementia (38) and delirium (42).

Apart from its known role in promotion of sleep, melatonin has also been implicated in neuronal maturation (43). Melatonin has also been shown to attenuate memory impairment in experimental models of AD (44), through stimulation of BDNF (Brain derived neurotrophic factor) and in inhibition of acetyl-cholinesterase production (45). Reduced daily melatonin production is associated with sleep disturbances and delirium in AD (46,47). Melatonin has also been shown to have a protective effect again production of the potentially toxic amyloid Aβ peptide (48) and against QA-mediated excitotoxic action. Lower production of adrenalin, due to lower levels of methyl B12, in turn can result in impaired thermoregulation seen in AD (49,50), as well as autonomic dysfunction and orthostatic hypotension, common conditions in AD and frontotemporal dementia (51), implicating the adrenergic system as being critically involved in the “sympathetic nervous system derangement” in the pathogenesis of AD (52).

Change in vitamin B12 levels in the frontal cortex of the brain during aging. (Reproduced from Zhang etal, 2016(53)).

6. Reduction in the formation of Iron-sulphur proteins and decreased energy production. Essential in energy production are the iron-sulphur proteins, aconitase, succinate dehydrogenase and Complex II in the electron transport chain. Formation of the iron-sulphur clusters is dependent upon the movement of sulphur out of the methylation pathway into the sulphation pathway, and this only occurs when levels of S-Adenosylmethionine (SAM) are high enough to stimulate cystathionine beta synthase to process homocysteine. In low methyl B12, however, this does not happen and the activity of aconitase is greatly decreased in low iron and low vitamin B12. This leads to massive loss of energy from the body as the substrates citrate and succinate accumulate, ready for processing, but are eventually lost into urine. This loss of energy contributes to the ongoing fatigue in dementia and speeds up the rate of autophagia.

Energy production in the brain slowly decreases as the deficiency in methyl B12 affects the transfer of dietary sulphur from methionine in the methylation cycle through to the production of the iron sulfur proteins, aconitase and succinate dehydrogenase, thus reducing their ability to process citrate and succinate for energy. Reduced aconitase activity is a feature of dementia, and this reduction correlates with decreased mini mental score estimations in those with progressive dementia. (Figure. Data from Mangialasche etal, (26)

7. Reduction in the formation of the neurotransmitter, Hydrogen Sulfide. Apart from the reduced formation of iron-sulphur proteins observed in low vitamin B12 levels, there is an accompanying reduction in the formation of hydrogen sulfide in the brain. Hydrogen sulfide is a very important gaseous neurotransmitter normally produced in the brain, appears to have a role in repair in the brain and has has been shown to attenuate cognitive defects (54,55) and to reduce homocysteine induced pathology in AD (56), hence reduction in hydrogen sulfide production in the progressive B12 deficiency would effectively reduce its neuro-restorative capacity. It has also been implicated in brain synaptic remodelling (56,57) and inhibit amyloid formation (58), all of which would be reduced in the developing B12 deficiency in the brain.

8. Peripheral Neuropathy. The quest for food for the brain and nerves does not restrict itself to those of the central nervous system and loss of myelin in peripheral nerves leads to the characteristic symptoms of vitamin B12 deficiency being common viz: ataxia, loss of cutaneous sensation, muscle weakness, diminished or hyperactive reflexes, spasticity, urinary or faecal incontinence, orthostatic hypotension, loss of vision and hearing (59). Many of these symptoms though are often ascribed to old age, and the symptoms are over-looked as signs of the on-coming dementia..

9. Energy Loss. The prolonged deficiency in vitamin B2 and vitamin B12 leads to increasing loss of energy as fats are processed ready for consumption, yet the B2 deficiency prevents this and the prepared fatty acids are excreted in the urine. Similarly, lack of activity of pyruvate dehydrogenase leads to excretion of pyruvate and lactate into the urine. The inability to process glucogenic amino acids leads to further energy loss as proteins are catabolized and inability to process them for energy leads to increased excretion of glycerate and oxalate into the urine. Much is "brought to the table" but the majority of the prepared fatty acids, glycolysis products and amino acids are simply excreted into urine and contribute to elevated urinary organic acids, and resultant pH drop in urine and increased availability of these organic acids for digestion by urinary tract yeast and bacteria. Urinary tract infections are very common, more indications of altered metabolism.

10. Intestinal Absorption. With prolonged vitamin B12 deficiency, there is a failure in the maturation of the small intestinal mucosa, with the appearance of villous atrophy and failure of maturation of villous epithelial cells, which are normally responsible for specific uptake of nutrients and vitamins (60). Even if the desire was there, the body is slowly losing its capability to absorb the very vitamins that it needs for survival.

The last supper

Finally the body exhausts itself of available energy for metabolism. The meal is over, there is no dessert, all the food has been eaten. The flame of life fizzles out, like the end of a sparkler. In a twist of fate, the body becomes its own “last supper”. Such was life, and such is death. RIP.

Epilogue

To some the above scenario may seem slightly over-dramatized, but in actuality the Biochemical parameters associated with the progression of Alzheimer's Disease fit the Autophagic Model very well.

The initiating factors in the progression of the disease may seem inconsequential at the time and may be a very small change in dietary intake, such as changing from iodized salt to more trendy Himalayan Rock salt (which despite its claims of mineral benefit has not iodine in it), changing from dairy milk (fortified with iodine in many countries) to soy milk (not fortified with iodine, and containing very little vitamin B2), changing from red meat to chicken (low in iron and vitamin B12), changing from gluten containing foods to gluten free (thus reducing the intake of vitamin B1, selenium and/or molybdenum), or even "going organic" (in many areas, such as the UK and many parts of Australia, the local soils are selenium deficient). Following these seemingly trivial events the story of decline begins. The disease may be very slow in onset and progress in an insidious fashion such that by the time symptoms become overt the initiating event is long forgotten.

The journey on the road to dementia can be a relatively long one. It is rather unusual in that no-body wants to go there, and the majority of people do not realize that they have started the journey. Most deny that they are "on the road" and what is more when they finally reach their destination, it is only the on-lookers and carers that realize that the destination has been reached. It is our hope that you do not start the journey, and if you do so, that you can recognize the signs and thereby get off the road and return to the start of the journey. Good luck to all, particularly the carers.

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