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Review
, 1842 (8), 1219-31

The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives

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Review

The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives

Russell H Swerdlow et al. Biochim Biophys Acta.

Abstract

Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it.

Keywords: Aging; Alzheimer's disease; Amyloid; Brain; Dementia; Mitochondria.

Figures

Figure 1
Figure 1. The mitochondrial cascade hypothesis
This hypothesis maintains individuals start out with a particular level of mitochondrial function, and that each individual's mitochondrial function declines at a particular rate. Eventually, mitochondrial decline surpasses a threshold and triggers the histologic changes associated with AD. The question mark indicates changes in APP, sAPPα, or Aβ may or may not further influence mitochondrial function. In FAD, if APP, sAPPα, or Aβ homeostasis changes induce mitochondria dysfunction, these changes may end up activating pathways that are also activated in LOAD.
Figure 2
Figure 2. The cybrid technique
An expandable cell line is treated with enough ethidium bromide to interfere with mtDNA replication, but not enough to prevent nuclear DNA replication. This depletes the cell line's endogenous mtDNA (shown by the absence of the red mtDNA circle within the mitochondrion in the top row), removes its mtDNA-encoded subunits (shown by the absence of the red rectangles within the mitochondrion in the top row), and generates a respiration-incompetent cell called a ρ0 cell. Incubating ρ0 cells with platelets in the presence of polyethylene glycol (PEG) allows platelet and ρ0 cell cytosols to mix. Platelet mitochondria contain mtDNA (shown as a green circle within the mitochondrion in the bottom row), which populates the ρ0 cell mitochondria, generates mtDNA-encoded respiratory chain subunits (shown as green rectangles within the mitochondrion in the bottom row), and restores respiratory competence. The new cybrid cell now contains mtDNA from the platelet donor, mtDNA-encoded respiratory chain subunits that match those of the platelet donor, its original nuclear DNA, and its original nuclear-encoded respiratory chain subunits.
Figure 3
Figure 3. Proposed mechanism through which respiratory decline can reduce glucose utilization
In the presence of respiratory chain impairment, which in AD could result from reduced COX activity, NADH generated within the mitochondria during the Krebs cycle cannot be oxidized. Increased NADH in the mitochondrial compartment, in turn, transmits indirectly to the cytosolic compartment. Shifting the cytosolic NAD+/NADH ratio towards NADH slows glycolysis, since glycolysis rates are to some extent determined by the cytosolic NAD+/NADH ratio. Reductions in both respiration and glycolysis fluxes results in less ATP production, and increases the cell ADP/ATP ratio.
Figure 4
Figure 4. The mitochondrial cascade hypothesis and Aβ accumulation
When age-associated mitochondrial decline first begins, neurons compensate by pushing their bioenergetic infrastructures. During this period of bioenergetic compensation, Aβ production increases and Aβ accumulates. As age-associated mitochondrial decline progresses, neurons can no longer bioenergetically compensate and bioenergetic-related parameters such as mitochondrial mass down-regulate. During this hypometabolic period, Aβ production decreases.
Figure 5
Figure 5. Aβ accumulation and cognitive decline timelines
Before notable cognitive decline commences, Aβ accumulation initiates, accelerates, peaks, and decelerates. By the time cognitive decline begins, Aβ accumulation virtually has virtually ceased.

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