Mitochondrial Dysfunction: The Link Between Aging and Alzheimer’s

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Background

Alzheimer’s Disease (AD) has been characterized for decades by the presence of histopathological alterations (extracellular amyloid- containing plaques and intracellular tangles of hyperphosphorylated tau-protein) leading to neurodegeneration (synaptic deficits and finally neuronal loss), as well as by severe cognitive deficits. However, to which extent one or both of the two histopathological hallmarks play a causative role remains unclear until now. The discovery of homozygotic risk genes in most of the very rare (probably less than 1%) cases of early onset Alzheimer’s disease which share increased production of β-amyloid (Aβ) as one (but probably not the only one) common property led to the amyloid-cascade hypothesis, assuming Aβ as the major if not the only causative factor for the development of AD. The possible contribution of aging as the major and well documented risk factor of AD has been neglected for decades. Biochemical mechanisms of “normal brain” brain aging and cognitive deficits of “normal brain aging” were seen as mechanisms not related at all to AD.

However, this simple Amyloid-hypothesis has been challenged in the recent years because of many observations in AD patients like: the lack of any correlation between the presence of amyloid-containing plaques and the clinical symptoms of AD, the findings that amyloid plaques were already present decades before the onset of clinical symptoms in AD, the failure of all AD-related treatment strategies to improve clinical symptoms even if AD-plaques were reduced, and the continuing neurodegeneration in AD brain even after removing Amyloid plaques by vaccination. Accordingly, other aspects of AD pathology, more closely related to the clinical symptoms of AD are currently investigated like the already mentioned synaptic deficits and other measures of neurodegeneration and their relationship to impairment of mitochondrial function. Probably the most important example for such an alternative concept is the “mitochondrial cascade hypothesis” put forward already years ago by Swerdlow and coworkers, assuming mitochondrial dysfunction with enhanced oxidative stress and elevated free radical (ROS) production as the major pathomechanism of AD which slowly develops by aging and finally leads to the clinical disease. Driven by genetic, environmental, and individual factors, mitochondrial dysfunction associated with elevated free radical (ROS) production cumulates in susceptible patients over many years. This process is self-accelerating as ROS will further damage mitochondria which respond with further elevation of ROS. At some point, elevated ROS production will reach a level where Aβ production increases due to β-secretase and Ɣ-secretase activation. Aβ in turn will further impair mitochondrial function and will aggregate to fibrils and finally to plaques. This scenario suggests that Aβ still has a causative role, but it is probably not the major player and definitively not the only player. It also seems to be a side product which once aggregated to plaques is without major functional relevance. This can easily explain that Aβ deposits themselves do not correlate with early signs of neurodegeneration or impaired cognition.
The major aspect of this concept relates to mitochondrial dysfunction as a major pathomechanism directly driving neurodegeneration and psychopathology independently of Aβ deposits, from the initial phase of the disease, long before a clinical diagnosis becomes possible to the later phases of mild to moderate dementia. Accordingly, mitochondrial dysfunction can lead to early signs of neurodegeneration or synaptic deficits, as well as distinct cognitive deficits without Aβ deposits being present, a new situation recently called “Suspected non-amyloid pathology (SNAP). On the other hand, nearly all patients of the later stages of AD do show Aß deposits.

In conclusion, it is a long and difficult road which leads from aging and age-related mitochondrial dysfunction to the clinical stages of AD. To clarify all the different parts the road is taken is of fundamental relevance to understand all aspects of AD and to find effective treatments.

Keywords: Alzheimer's, Mitochondria, Neurodegeneration

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