Theories About Neurodegeneration

(December 5, 2016)

picassoIt is still unknown why some people age with minimal or no disability. These lucky people are 80 years old and walk fluently, speak fluently, learn and think fluently. They may share a huge accumulated experience along their prolonged existence. They can read and play with their grandchildren or great-grandchildren. (At his 80s, Picasso still created valuable works of art, and pursued women).

The other side is quite sad. The Alzheimer’s Association estimates (“2016 Alzheimer’s Disease Facts and Figures”, http://www.alz.org/facts/) that 5.4 million Americans suffer Alzheimer’s. At age 65 or older, one in nine people have Alzheimer’s disease (11%). However, the odds increase even more (up to 32%) by passing the age of 85 years.

The statistics are not less alarming for Parkinson’s disease. According to the Parkinson’s Disease Foundation, up to one million Americans suffer from Parkinson’s disease. 60,000 are diagnosed with Parkinson each year, and more than 10 million people worldwide live with this terrible affliction. Even worse, an estimated of 4% of these patients have less than 50 years old.

Other neurodegenerative diseases may have not such an alarming prevalence, but they are equally devastating diseases.

In this section we are going to show the most compelling theories about neurodegeneration. Since it is a big amount of information, we are going to present them in partial deliveries. The first one is about cyrcadian rythm, sleeping and aging.

Cyrcadian Rythm, Sleeping and Aging

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Taken from: Russel J. Reiter, Rosales-Corral Sergio, et al., Circadian dysregulation and melatonin rhythm suppression in the context of aging” (2016), in press.

Think in the morning. Act in the noon. Eat in the evening. Sleep in the night.

                                                     William Blake

The rhythm of life rules everything, a whole complex organism and every single cell. Our internal clocks tell us not only when we should go to sleep, but determines our development and growing, our maturity and the time to reproduce as well as they mark the years and the stages of an entire life. These biological oscillations range from milliseconds to minutes, from minutes to hours, days, even years.

Recent investigations have found that disruptions of normal circadian rhythms and sleep cycles are consequences of aging and may lead to neurodegenerative conditions. It is well known that sleep disturbances and circadian rhythm dysfunction are common features of Parkinson’s, Alzheimer’s and Huntington’s diseases, but this new knowledge reveals that sleep disturbances and circadian rhythm malfunction by themselves may actually drive pathological processes early in the course of these diseases (1).

For example, it is well known the endogenous circadian clock modulates cognitive performance over the daily 24-h cycle (2). There is a set of circadian clock genes, named by ad-hoc names, such as per (period), or tim (timeless), Clock (Circadian Locomotor Output Cycles Kaput), or CYCLE (CYC). By ticking in synchronized oscillations in different brain areas, they define precise regulation pathways, being critical to the generation of circadian rhythms. If disrupted by mutation, these circadian clock genes show significant implications for mental and physical health. For example, jet lag or shift work schedules disrupt the normally synchronous waves of gene expression among the different areas, and lost temporal adaptation.

If synchronicity and temporal adaptation are disturbed, fails the circadian modulation of events of signaling inside the cell. One of these events controls of the expression of a protein known as CREB, which it works as a transcription factor (a key protein with the ability to cross the nuclear membrane and activate the transcription of a particular gene). CREB participates in the formation of memory and learning processes by regulating the called long-term potentiation (LTP). This is a complex mechanism by which connections (synapses) between two neurons, develop patterns of activity which become by themselves into pieces of information between those interacting neurons. Once this mechanism fails, both cognitive and affective functioning fail as well.

Long-term depression (LTD) and long-term potentiation (LTP), are key for adaptive motor control and procedural memory. According to Picconi and co-workers (3) “the impairment of these two forms of synaptic plasticity in the nucleus striatum could account for the onset and the progression of motor and cognitive symptoms of Parkinson’s disease (PD), characterized by the massive degeneration of dopaminergic neurons.”

The disruption of the core circadian clock in the brain facilitates neurodegeneration. Musiek and co-workers (4) have found in mice without the brain-specific Bmal1 gene (knockout mice) that these animals developed a severe reaction of astrocites in cortex (these cells specialize in vigilance and order within the central nervous system). The above in addition to oxidative damage and synaptic degeneration. Such events were associated with impaired circadian transcription of several redox defense genes (REDOX is a oxidation-reduction reactions chain, indispensable to keep the physiological equilibrium in cells, neutralizing the incessant oxidative pressures). These authors conclude that declines in circadian function, as seen in aging or AD, might exacerbate neurodegeneration via decreased BMAL1-mediated transcription. However, they assure that “further studies are needed to examine the regulation of clock genes in AD, the downstream mechanisms mediated by the circadian clock in neurons and glia, and how circadian dysfunction regulates Aβ, tau, and other AD-related pathways”.

Interestingly, neurodegeneration as observed in Alzheimer’s starts when levels of melatonin, the key biochemical circadian regulator, decrease significantly [5].

Melatonin production declines with age because of dysfunction of the sympathetic regulation of pineal melatonin synthesis by the suprachiasmatic nucleus (SCN), a condition probably linked to early Alzheimer’s disease (AD) stages, once that the reactivation of the circadian system using light therapy and melatonin has shown promising positive results [6]. Firmly established as the key mediator controlling circadian rhythms [7], it has been discovered that melatonin, a small, lipophilic molecule, also had the capacity to directly scavenge dangerous free radicals. Almost immediately, a link between melatonin’s hydroxyl radical-scavenging activity and aging was envisioned as well as realizing that aging and Ab-induced oxidative stress play a key role in AD as well.

[1] Musiek ES, Holtzman DM. Mechanisms linking circadian clocks, sleep, and neurodegeneration. Science. 2016; 354(6315):1004-8.

[2] Kyriacou CP, Hastings MH. Circadian clocks: genes, sleep, and cognition. Trends in cognitive sciences. 2010; 14(6):259-67.

[3] Picconi B, Piccoli G, Calabresi P. Synaptic dysfunction in Parkinson’s disease. Adv Exp Med Biol. 2012; 970:553-72.

[4] Musiek ES, Xiong DD, Holtzman DM. Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Experimental & molecular medicine. 2015; 47:e148.

[5] Rosales-Corral SA, Acuna-Castroviejo D, Coto-Montes A, et al. Alzheimer’s disease: pathological mechanisms and the beneficial role of melatonin. Journal of pineal research. 2012; 52(2):167-202.

[6] Wu YH, Swaab DF. The human pineal gland and melatonin in aging and Alzheimers disease. J Pineal Res 2005; 38:145–152.

[7] Reiter RJ, Cuna-Castroviejo D, Tan DX et al. Free radical- mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system. Ann N Y Acad Sci 2001; 939:200–215.

 

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