Related Experiment Video
Updated: May 7, 2026
08:48
Using Live Cell STED Imaging to Visualize Mitochondrial Inner Membrane Ultrastructure in Neuronal Cell Models
Published on: June 30, 2023
The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives
Russell H Swerdlow1, Jeffrey M Burns2, Shaharyar M Khan3
1Departments of Neurology and Molecular and Integrative Physiology, and the University of Kansas Alzheimer's Disease Center, University of Kansas School of Medicine, Kansas City, KS, USA; Department of Biochemistry and Molecular Biology, University of Kansas School of Medicine, Kansas City, KS, USA.
Biochimica Et Biophysica Acta
|September 28, 2013
Summary
The Alzheimer's disease (AD) mitochondrial cascade hypothesis proposes that mitochondrial dysfunction, influenced by genetics and environment, triggers amyloid precursor protein (APP) accumulation. This perspective suggests current AD treatments targeting amyloid may be less effective.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- The Alzheimer's disease (AD) mitochondrial cascade hypothesis was first proposed a decade ago.
- This hypothesis links genetic inheritance and environmental factors to mitochondrial function and its decline over time.
- It posits that mitochondrial dysfunction is a key initiator of the amyloid cascade in sporadic, late-onset AD.
Purpose of the Study:
- To review the current status of the mitochondrial cascade hypothesis for Alzheimer's disease.
- To discuss the hypothesis in light of recent advancements in AD biomarkers, diagnostic criteria, and clinical trials.
- To offer a unique perspective on the nature and treatment of sporadic, late-onset AD.
Main Methods:
- Review of existing literature on the mitochondrial cascade hypothesis.
- Analysis of recent AD biomarker studies.
- Discussion of current AD diagnostic criteria and clinical trial outcomes.
Main Results:
- The hypothesis predicts that biomarker changes observed in AD reflect natural brain aging processes.
- New AD definitions may clinically stage brain aging rather than a distinct disease process.
- Interventions aimed at removing beta-amyloid (Aβ) are predicted to have minimal impact on cognitive trajectories.
Conclusions:
- Mitochondrial function is proposed as the trigger for the amyloid cascade in Alzheimer's disease.
- The hypothesis suggests that targeting amyloid may not be the most effective treatment strategy.
- Understanding mitochondrial dynamics offers a novel perspective for managing sporadic, late-onset AD.
Related Concept Videos
01:37Mitochondria
Mitochondria are eukaryotic cellular organelles that are known to produce energy through a process called oxidative phosphorylation. Besides their primary function, mitochondria are involved in various cellular processes, including cell growth, differentiation, signaling, metabolism, and senescence. Age-related changes cause a decline in mitochondrial quality and integrity due to increased mitochondrial mutations and oxidative damage. Thus, aging can severely impact mitochondrial functions,...
01:46Electron Transport Chain: Complex I and II
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
01:26Alzheimer's Disease: Overview
Alzheimer's Disease (AD) is a continually advancing neurodegenerative disorder, distinguished by escalating memory loss, cognitive dysfunction, and dementia. The disease unfolds in three stages: preclinical, mild cognitive impairment (MCI), and dementia. Its onset is insidious, and the progression gradual, with the cause not well explained by other disorders.
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ and tau...
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ and tau...
01:23Alzheimer Disease ll: Pathophysiology
Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neuritic plaques and intracellular neurofibrillary tangles.Neuritic plaques form in the cerebral cortex and around blood vessels. These plaques contain a dense core of beta-amyloid (Aβ)—a toxic protein fragment that clumps outside neurons. The core is surrounded by damaged neuronal extensions, as well as reactive astrocytes and microglia. Abnormal...
01:45Mitochondrial Membranes
A single mitochondrion is a bean-shaped organelle enclosed by a double-membrane system. The outer membrane of mitochondria is smooth and contains many porins - the integral membrane transporters. Porins enable free diffusion of ions and small uncharged molecules through the outer mitochondrial membrane but limit the transport of molecules larger than 5000 Daltons. Further, the outer mitochondrial membrane forms a unique structure called membrane contact sites with other subcellular organelles,...
01:19Translocation of Proteins into the Mitochondria
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...