The Mitochondrial Hypothesis: Is Alzheimer’s a Metabolic Disease?

Originally published on the PLOS Neuroscience Community

Despite decades of research devoted to understanding its origins, Alzheimer’s disease remains a daunting and devastating neurological mystery, ranking as the sixth leading killer of Americans. Countless therapeutic attempts, each designed with fresh anticipation, have repeatedly failed. A common thread across many of these drugs is their targeting the defining marker of the disease, amyloid plaques – those nasty extracellular deposits of beta-amyloid protein that invariably present in the Alzheimer’s brain and are thought to be toxic to neurons. Given the frustrating loss of research money, time and effort, many scientists agree it’s time to stop running circles around the amyloid hypothesis and begin seriously considering alternative explanations. One such theory showing increasing promise is the “mitochondrial hypothesis”. Its proponents posit that mitochondrial dysfunction lies at the heart of neural degeneration, driven by metabolic abnormalities which lead to classic Alzheimer’s pathology.

Steps by which mitochondrial function may lead to Alzheimer's. Based on the model outlined in Swerdlow et al (2010).

Steps by which mitochondrial function may lead to Alzheimer’s. Based on the model outlined in Swerdlow et al (2010).

Thank mom for your genetic risk

The first hints at this possibility arose from epidemiological observations about the genetic patterns of Alzheimer’s prevalence. These findings suggest that genetic influences may include more nuanced interactions than the better-known contributions from genes such as ApoE and TOMM40. Although both parents determine genetic risk, your likelihood of getting Alzheimer’s is much higher if the affected parent was your mother. This argues strongly that some maternal element underlies the association. Mitochondrial DNA is a logical target, as this subset of DNA is solely passed down from the mother. Many features of Alzheimer’s show this same maternal-dominant inheritance; those whose mother (but not father) had the disease also show reduced glucose metabolism and cognitive function, as well as elevated PIB uptake (a marker of amyloid) and brain atrophy.

Are metabolic enzymes the pathological trigger?

So if mitochondrial dysfunction initiates the Alzheimer’s cascade, what are the steps leading from metabolic disruption to neurodegeneration and ultimately, dementia? Studies point to cytochrome oxidase – a key enzyme for mitochondrial metabolism that’s encoded by both mitochondrial and nuclear DNA – as a likely trigger for early pathological events. Studies suggest that the enzyme is dysfunctional in the earliest disease stages; its activity is reduced not just in those with Alzheimer’s, but even in asymptomatic individuals who are at genetic risk for the disease or had a mother with Alzheimer’s. Furthermore, this stunted activity is linked directly to mitochondrial (or maternal) genetic contributions. By simply replacing the mitochondrial portion of the cytochrome oxidase DNA with DNA from Alzheimer’s patients, an otherwise normal cell will now have reduced cytochrome oxidase activity.

Bridging metabolism to Alzheimer’s pathology

For the mitochondrial theory to hold water, it must critically account for the classic pathological markers that define Alzheimer’s and have shaped traditional disease models – namely, amyloid plaques, tau tangles and brain atrophy. Indeed, growing evidence is elegantly bridging altered mitochondrial function to these key markers. For instance, disrupting mitochondrial electron transport chain activity (if you’ve forgotten your basic biochemistry, this is essential to cell metabolism) increases phosphorylated tau. What’s more, inhibiting cytochrome oxidase promotes a host of neurotoxic downstream effects including increased oxidative stress, apoptosis and amyloid production. Conversely, there’s also evidence that amyloid disrupts electron transport chain and cytochrome oxidase function, posing a chicken-or-egg conundrum. Amyloid has been found to buddy-up to mitochondria, but which comes first, the amyloid or the mitochondrial dysfunction, isn’t entirely clear. Both events occur early in the disease process, even before individuals show any symptoms of cognitive impairment. Whatever the mechanism, neurons from Alzheimer’s patients show signs of increased mitochondrial degradation. And when a neuron’s “powerhouse” begins to degrade, it cannot possibly support normal cognitive function.

A promising path for progress

It remains to be seen whether metabolic dysfunction is the key to unlocking the mechanisms of Alzheimer’s, and to ultimately developing effective therapeutics. While the current evidence is quite promising, many of the issues underlying the failure of other theories (poor translation of animal findings to humans, the challenge of identifying causal mechanistic pathways, etc.) similarly apply to the mitochondrial hypothesis. But at the very least, the proposal lays new ground for neuroscientists to continue progressing forward after a recent history of frustrating dead-ends. Even if mitochondria don’t hold the answer researchers have been seeking, understanding its contributions to Alzheimer’s pathology can only bring us closer to solving the mystery of this devastating disease.

References

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Debette S et al. (2009). Association of parental dementia with cognitive and brain MRI measures in middle-aged adults. Neurology. 73(24):2071-8. doi: 10.1212/WNL.0b013e3181c67833

Edland SD et al (1996). Increased risk of dementia in mothers of Alzheimer’s disease cases: evidence for maternal inheritance. Neurology. 47:254–6. doi: 10.​1212/​WNL.​47.​1.​254

Hirai K et al. (2001). Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci. 21(9):3017-23

Hogliner GU et al. (2005). The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy. J Neurochem. 95(4):930-9. doi: 10.1111/j.1471-4159.2005.03493

Honea RA et al. (2010). Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease. Neurology. 74(2):113-20. doi: 10.1212/WNL.0b013e3181c918cb

Kish SJ et al. (1992). Brain cytochrome oxidase in Alzheimer’s disease. J Neurochem. 59(2):776-9. doi: 10.1111/j.1471-4159.1992.tb09439

Mosconi L et al (2007). Maternal family history of Alzheimer’s disease predisposes to reduced brain glucose metabolism. Proc Natl Acad Sci. 104(48):19067-72. doi: 10.1073/pnas.0705036104

Mosconi L et al. (2010). Increased fibrillar amyloid-{beta} burden in normal individuals with a family history of late-onset Alzheimer’s. Proc Natl Acad Sci. 107(13):5949-54. doi: 10.1073/pnas.0914141107

Mosconi L et al. (2011). Reduced Mitochondria Cytochrome Oxidase Activity in Adult Children of Mothers with Alzheimer’s Disease. J Alzheimers Dis. 27(3): 483–490. doi: 10.3233/JAD-2011-110866

Roses AD et al (2010). A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer’s disease. Pharmacogenomics J. 10(5): 375–84. doi: 10.1038/tpj.2009.69

Swerdlow RH et al. (1997). Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology. 49(4):918-25. doi: ​10.​1212/​WNL.​49.​4.​918

Swerdlow RH, Burns JM and Khan SM (2010). The Alzheimer’s Disease Mitochondrial Cascade Hypothesis. J Alzheimers Dis. 20 Suppl 2:S265-79. doi: 10.3233/JAD-2010-100339

Swerdlow RH. (2012). Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer’s disease. Antioxid Redox Signal. 16(12):1434-55. doi: 10.1089/ars.2011.4149

Valla J et al. (2010). Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE ε4 allele, the major late-onset Alzheimer’s susceptibility gene. J Alzheimers Dis. 22(1):307-13. doi: 10.3233/JAD-2010-100129

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  1. […] Association Volunteer AdvocateRodent models of neuroinflammation for Alzheimer’s diseaseThe Mitochondrial Hypothesis: Is Alzheimer’s a Metabolic Diseasebody { background: […]

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