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Neurodegenerative Diseases Being Treated with

High Doses of NAD+

Not Surprisingly, with Major Success!


Both Diseases Feature Poor Mitochondria and a Poor Microbiota

Although both Alzheimer’s and Parkinson’s can progress toward dementia, accompanied by widespread damage (D’Andrea, 2016; Weil et al., 2017), they differ in which part of the brain they damage the most. Alzheimer’s is best known for degeneration of the hippocampus (Figure 2A) and resulting deficits in the formation of new memories (D’Andrea, 2016); Parkinson’s with that of the pars compacta portion of the substantia nigra (Figure 2B) and resulting deficits in one’s ability to move about (Dickson et al., 2009; Poewe et al., 2017). Yet these neurological differences actually highlight yet again how much the two diseases have in common. Most of the energy our body and brain run on is furnished by our mitochondria – entities inside our cells that evolved from bacteria (Lane, 2015). And it so happens that the hippocampus contains unusually low levels of a protein – implicated in Alzheimer’s disease (Acker et al., 2019) – that helps neurons and their mitochondria obtain oxygen (Burmester et al., 2000). This, then, leaves these hippocampal mitochondria particularly vulnerable to dysfunction (Acker et al., 2019). Likewise, the pars compacta hosts exceptionally large neurons, which require exceptionally large amounts of energy, and these neurons’ mitochondria may therefore also be particularly vulnerable to dysfunction (Pacelli et al., 2015; Rietdijk et al., 2017; Shlevkov and Schwarz, 2017; Gonzaìlez-Rodriìguez et al., 2021). This is especially the case because calcium levels in these neurons tend to be higher than elsewhere, and this stimulates alpha-synuclein buildup (Surmeier et al., 2017). In Parkinson’s, much smaller neurons in nearby brain areas tend to be spared (Pacelli et al., 2015; Rietdijk et al., 2017; Shlevkov and Schwarz, 2017).


Figure 2. Location in the brain of (A) the hippocampus and (B) the midbrain (containing the substantia nigra), shown in red. The images are generated by Life Science Databases from the Anatomography website maintained by Life Science Databases (Creative Commons):;

Although also heavily implicated in virtually every other mental affliction, from chronic psychological stress and fatigue to schizophrenia and autism (Kramer and Bressan, 2018), mitochondrial dysfunction typically both accompanies and precedes Alzheimer’s and Parkinson’s disease (see section “Poor Mitochondria Means a Poor Microbiota”). Such mitochondrial dysfunction can have various different causes, but one of them is an abnormal presence of amyloids (Wong and Krainc, 2017; Bernal-Conde et al., 2020; Huang et al., 2020; Quntanilla and Tapia-Monsalves, 2020; Szabo et al., 2020; Borsche et al., 2021; Feng et al., 2021; Nguyen et al., 2021; Zaretsky and Zaretskaia, 2021). The question arises, however, what causes this abnormal presence. An important part of the answer, it appears, is infection and inflammation (see section “The Main Problem Is Pathogens, Not Amyloids”).

Pathogens can invade us through various points of entry, but a major one is the gut. Primarily in the intestines, we house an estimated 38 trillion microbes (Sender et al., 2016), among which at least 2,172 known species (Hugon et al., 2015), comprising about as many (small) microbial cells as we have (large) human ones (Sender et al., 2016). In addition, these intestines leave space for an even more diverse and numerous collection of viruses (Cryan et al., 2019). Most of these are phages and prey on our gut microbes without affecting us directly (Cryan et al., 2019) but they nonetheless have been reported to affect their host’s gut-blood barrier (Fitzgerald et al., 2019). Even at the best of times, the community of microbes (microbiota) in the gut is not a harmless community of symbionts: we possess a protective gut-blood barrier to keep them out of our bloodstream, and because that is not good enough, we also have a blood-brain barrier to keep them out of our brain. To ease nutrients through, the gut-blood barrier is only one-cell-thick and semipermeable (Groschwitz and Hogan, 2009). In compensation, the intestine (especially the large one, the colon, in which most of the gut microbiota resides) is coated with a layer of sticky mucus, which helps protect the gut-blood barrier from pathogen invasion (von Martels et al., 2017; Kowalski and Mulak, 2019). Most importantly, the barriers of both the small and the large intestine are protected by a heavy presence of the immune system (Kowalski and Mulak, 2019).

This system, however, can only do its job if it is furnished with sufficient energy, a task entrusted mostly to mitochondria. Counterintuitively, some of these mitochondria have a sort of brake on their energy production and release these brakes only when needed (see section “Poor Mitochondria Means a Poor Microbiota”). If the mitochondria fail to deliver the energy the immune system needs, an unhealthy change in the gut microbiota results, known as dysbiosis (see section “Poor Mitochondria Means a Poor Microbiota”). The health of the microbiota thus depends on that of the mitochondria, but because mitochondria need nutrients and are harmed by pathogens, their health also depends on that of the microbiota. For how long the interaction between mitochondria and microbiota remains beneficial, and we can keep neurodegenerative disease at bay, depends in part on the quantity of food we eat (see section “Mitochondria’s Oxygen Consumption Benefits the Microbiota”). It also depends on how rich this food is in, for example, fibers (see section “The Microbiota’s Fatty Acids Benefit Mitochondria”), fatty acids (see section “The Microbiota’s Fatty Acids Benefit Mitochondria”), and protein (see section “The Microbiota’s Hydrogen Sulfide Can Either Benefit or Harm Mitochondria”). With age, both mitochondria and the microbiota deteriorate, and gut pathogens then have multiple options to either indirectly or directly wreak havoc on the brain (see section “Trouble in the Gut Is Trouble in the Brain”). Indeed, Alzheimer’s (Fulop et al., 2018; Moir et al., 2018; Ashraf et al., 2019; Cryan et al., 2019; Li et al., 2021) and Parkinson’s (Cardoso and Empadinhas, 2018; Nair et al., 2018; Cryan et al., 2019; Lubomski et al., 2019; Huang et al., 2021; Munoz-Pinto et al., 2021), along with many other mental afflictions (Vuong et al., 2017; Cryan et al., 2019), tend to be both accompanied and preceded by not only mitochondrial dysfunction but also dysbiosis and intestinal disease (see also Vogt et al., 2017; Villumsen et al., 2019; Shen et al., 2021).


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