Blockade of protein importation, calcium overload, increased production of toxic reactive oxygen species, and reduced ATP and membrane potential are aspects of mitochondrial dysfunction found in AD.
Loan Vaillant-Beuchot (Institute of Molecular and Cellular Pharmacology, University of Nice, France) described how accumulation of C-terminal fragments from the amyloid precursor protein (APP) triggers changes in mitochondrial structure and function.1 This occurs in both in vitro and in vivo models of AD and in affected human brains.
Effects of APP fragments on mitochondria could be the etiological trigger in AD
Do APP fragments drive mitochondrial dysfunction?
Work on cell lines carrying relevant mutations and in transgenic mice shows that APP C-terminal fragments also enhance production of reactive oxygen species, and inhibit the mitophagy which should lead to clearance of defective mitochondria -- in part by preventing fusion of mitochondria with lysosomes.
These effects of C-terminal fragment accumulation – induced experimentally either by pharmacological blockade of the APP cleaving enzyme γ-secretase or by overexpression -- are independent of amyloid-β, although this aberrant protein, along with tau, can induce defective mitophagy.
In post mortem studies of the brains of people who had sporadic AD, the French group also found accumulation of APP fragments and a molecular signature consistent with failure of mitophagy.
Accumulation of APP C-terminal fragments could be a therapeutic target, along with countering defective mitochondrial function and mitophagy.
Mitochondrial copy number is reduced in the AD cortex
Further evidence of mitochondrial dysfunction
Hans-Ulrich Klein and colleagues (Columbia University Medical Center, New York, USA) told ADPD2021 of evidence from a longitudinal aging cohort and AD case-control studies that mitochondrial copy number in the cortex of patients with AD is reduced. This reduction is associated with tau pathology – but not with amyloid. Copy number had an independent effect on cognition.
Apoptosis is the main mechanism of neuronal loss in AD. The tumor suppressor protein p53 plays a key role, and accumulates in the brains of people with the disease. So could p53 also become a novel drug target?
As described by Rebeca Lapresa (University of Salamanca, Spain), Aβ oligomers promote activation of cyclin dependent kinase-5 (Cdk5), which induces p53 phosphorylation and stabilization, leading to mitochondrial dysfunction and neuronal apoptosis.2 We also know that p53 modulates neuronal susceptibility to Aβ toxicity.
p53 added to list of targets
Dr Lapresa and colleagues have shown that mitochondrial dysfunction and apoptosis of neurons are prevented by genetic or pharmacological inhibition of either p53 or Cdk5 activity.
Inhibiting the Cdk5-p53 pathway may be a way of preventing Aβ-induced neurodegeneration
In trying to combat AD, we are not short of potential targets. To intraneuronal neurofibrillary tangles composed of tau, extraneuronal Aβ plaques, synaptic failure, oxidative stress and microglia-regulated neuroinflammation – to name only some – we can now clearly add mitochondrial dysfunction.3
And it may be that effective intervention in AD will require that we tackle several of these targets simultaneously, and early in the course of disease.
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