Relationships between Mitochondrial Dysfunction and Neurotransmission Failure in Alzheimer’s Disease

Abstract

Besides extracellular deposition of amyloid beta and formation of phosphorylated tau in the brains of patients with Alzheimer's disease (AD), the pathogenesis of AD is also thought to involve mitochondrial dysfunctions and altered neurotransmission systems. However, none of these components can describe the diverse cognitive, behavioural, and psychiatric symptoms of AD without the pathologies interacting with one another. The purpose of this review is to understand the relationships between mitochondrial and neurotransmission dysfunctions in terms of (1) how mitochondrial alterations affect cholinergic and monoaminergic systems via disruption of energy metabolism, oxidative stress, and apoptosis; and (2) how different neurotransmission systems drive mitochondrial dysfunction via increasing amyloid beta internalisation, oxidative stress, disruption of mitochondrial permeabilisation, and mitochondrial trafficking. All these interactions are separately discussed in terms of neurotransmission systems. The association of mitochondrial dysfunctions with alterations in dopamine, norepinephrine, and histamine is the prospective goal in this research field. By unfolding the complex interactions surrounding mitochondrial dysfunction in AD, we can better develop potential treatments to delay, prevent, or cure this devastating disease.

The biological pathways of Alzheimer disease: a review

“…Further, OS exert its effect on the choline recycling from the synapse processes, leading to ACh deficiency [200] . In late stage AD, levels of presynaptic high-affinity choline transporter 1 (CHT1) were observed to be decreased in synaptosomes in the hippocampus and neocortex of humans [201] .…”

“…For instance, it was observed that the expression and function of key enzymes in the glycolytic cascade is reduced with high ROS levels [32] , [216] , [217] . Energy alterations were also linked to a decreased functionality of enzymes related to TCA cycle, which lead neurons to a hypometabolic state [200] , [218] – [222] . High Cerebrospinal fluid pyruvate and lactate has been widely reported in AD patients compared with healthy elderly controls [223] .…”

Interdisciplinary Research in Alzheimer’s Disease and the Roles International Societies Can Play

“…The combination of pathological and clinical features, however, does not overcome the issue of defining the disease—defining a “disease” requires identification of the causes [ 15 ]. It has long been thought that AD is caused by the deposition of amyloid-β [ 3 , 4 ]. However, amyloid-β can be found in healthy older subjects [ 16 , 17 ], and there seems to be little to no correlation between amyloid load and the degree of cognitive decline in AD patients [ 18 , 19 ].…”

“…Other markers like tau and neurofibrillary tangles correlate better to cognitive decline in AD patients, yet this still does not establish a causative role, and may simply reflect a pathological feature of another causative process [ 15 ]. This lack of understanding of the causes of AD brings difficulties in itself, yet it is further compounded by the fact that it prevents the development of good experimental models [ 3 , 4 ]. Transgenic mice are one of the most widely used models in AD, and their use has been extensively discussed by Drummond and Wisniewski [ 20 ], yet they and others have noted issues in the lack of consistency of these experimental models or their lack of relevance (e.g., dependence on familial AD mutations but most cases tend to be sporadic).…”

“…The number of people with dementia is expected to more than triple by 2050, which will inevitably have enormous social and economic costs [ 2 ]. The experimental research in AD has been highly skewed in favor of Amyloid Cascade Hypothesis and the use of transgenic AD models [ 3 , 4 ]. At the same time a huge body of epidemiological data on various metabolic and environmental risk factors of AD has been somewhat ignored to develop suitable models or to formulate new treatment strategies for AD [ 5 ].…”