1 A different view on the origin of the sporadic form of Alzheimer's disease: Neuronal mitochondrial energetics

1.1 Introduction

There are various entities attributed to Alzheimer's disease. A purely familial form of the disease differs from the sporadically occurring one. The latter appears mainly in old age and has a multifactorial genesis.

Accordingly, the sporadic form of Alzheimer's disease is an agerelated neurodegenerative disorder of the brain. Clinically, it is characterized by a progressive loss of cognitive abilities and associated behavioral and neuropsychological symptoms. Consistent with the amyloid theory, its pathognomy results from protein misfolding of extracellularly stored amyloid (Aß) plaques and intracellular neurofibrils formed by hyperphosphorylated tau protein. This cascade is partly hypothetical (1) and therefore controversial. In particular, the circumstances of the mechanisms that lead to the degradation of a neuron have not yet been fully elucidated. Also why the presence of plaques and the onset of cognitive impairment are not necessarily correlated. Above all, cognitive abilities cannot be significantly improved after therapeutic administration of biologics for plaques reduction or removal, which is tantamount to a falsification of the corresponding hypothesis.

This is in contrast to the hypothesis of nerve cell damage due to mitochondrial bioenergetic dysfunction (2). In terms of development history, the dynamic aspect is to be emphasized. The effects of mutations in the mitochondrial DNA, aging and, in particular, the energy supply of a cell are taken into account. Mitochondria are considered the power plants of a cell and cover the high energy requirements of neurons in the brain.

In the case of multifactorial upregulated oxidative phosphorylation, the rate of reactive oxygen species increases the likelihood of mutations in mitochondrial DNA. The resulting aging of a cell and the change in the specific energy-supplying property of the mitochondria have a degeneratively destructive effect on the neurons of the brain. They become senescent or die from programmed cell death.

All life derives from complex processes and requires only a few ingredients to form robustly. According to recent findings, animal and plant life originally arose through quantum mechanical effects such as "tunneling" or "coherence", while competition and stress were constant drivers of natural selection. A milestone in this development was the emergence of the eukaryotes and thus the mitochondria. Over time, the latter became the key energy supplier of a cell and were also able to process, store and use information. Whether dysfunctional mitochondria may be at the forefront of the cascade in the sporadic form of Alzheimer's disease is the subject of this systematic review. Nevertheless, the result could indicate a typical chicken-and-egg problem. Then the question of the actual substance immediately arises.

1.2 What is currently known about Alzheimer's disease?

1.2.1 Amyloid cascade

Alzheimer's disease regularly presents as a predominantly age-related, progressive and neurodegenerative disorder. As the disease stride ahead orientation, communication skills, autobiographical identity and personality traits become impaired. Histologically, Amyloid-plaques are found extracellularly in nerve tissue. They consist of misfolded ß-amyloid peptide. In contrast, neurofibrils of hyperphosphorylated tau proteins are localized intracellularly.

Amyloid is a protein-polysaccharide complex of diverse origin. To date, more than 25 such proteins of different structure and function have been described, including immunoglobulins, serum transport proteins, apolipoproteins, hormones and proteases. Normally, amyloid is present in dissolved form in blood serum. A pathological situation results from an overproduction of misfolded and dysfunctional amyloidogenic proteins. Due to a conformational change of the original protein with conversion from α-helical structures to β-sheet structures, gives rise to insoluble complexes in form of microscopic fibers. These can no longer be adequately degraded or excreted and are therefore deposited in interstitial or even functional tissues (3).

In Alzheimer's disease, hard amyloid plaques are found extracellularly in the brain. ß-Amyloid (Aß) is a protein fragment of the amyloid precursor protein (APP) that is also involved in the formation of junctions between neurons. APP can be cleaved by three different enzymes: physiologically by an α-secretase close to the membrane, under which its n-terminal end enters the extracellular space as soluble sAPP and is normally disposed of. In contrast, there is an amyloidogenic pathway via β -secretase, which, as a membrane-bound enzyme, cuts off APP in the extracellular space and releases an extracellular, soluble fragment. Then the transmembrane region of APP is separated out by γ-secretase. Faulty cleavage at the n-terminal and c-terminal end by β-secretase and γ-secretase gives rise in β-amyloids: amyloid Aβ-1-40 and Aβ-1-43 as well as the neurotoxic Aβ-1-42.

These counteract all other defense mechanisms and therefore remain in place. Extracellularly, A β -1-42 molecules initially form smaller, oligomeric aggregates. They then polymerize into large, hard and insoluble amyloid plaques between neurons, which eventually become surrounded by abnormal neuronal processes and glia cells. Immune cells originating from microglia are activated and then trigger inflammatory tissue-damaging reactions in the brain. Similarly, amyloid is deposited in the walls of small blood vessels. Inflammatory processes reduce their permeability with negative effects on the oxygen and energy supply (4). According to recent findings, β-amyloid also accumulates in neurons. The relevance of this finding has not been conclusively clarified. These may be relics of the immune system active in the brain (5).

In addition, Aβ-1-42 plaques cause increased permeability of Ca2+ ions in neuronal membranes affecting synaptic signaling, as shown in the hippocampus. This impairs short and long-term memory. Otherwise, Ca2+ ions are essential for intracellular signaling cascades. Increased influx can activate kinases, e.g., microtubules affinity-regulating kinase (MARK), which then hyperphosphorylate tau protein, a microtubule associated protein (MAP). This process gradually leads to their detachment from the cytoskeletal structure, resulting in aggregation into neurofibrillary tangles. The tau protein is responsible for maintaining the structure of the microtubules. Microtubules form the cytoskeleton by transporting cell nutrients and other molecules throughout the cell. Excessive loading of tau protein with phosphate groups disrupts many stabilization and transport processes until finally the cytoskeleton with the microtubular structures collapses and causes neuronal cell death (6).

Taken together, these processes lead to the destruction of tissue architecture. The brain shrinks by up to 20% of its original volume, while the vertebral sulci on its surface deepen and the cerebral ventricles expand. Morphologically it atrophies. Gaps left by the death of neurons are filled by proliferating glial supporting tissue. Topographically, the hippocampal region is affected early. Cortical areas of the temporal and frontal lobes are involved in processing. Later also deeper brain structures, accompanied by the destruction of synapses, which are used for the transmission and processing of information. In the lower cerebral cortex is the basal nucleus Meynert, whose nerve cells produce the messenger substance acetylcholine. If cells in this nucleus die, acetylcholine loses its function as a neurotransmitter. Finally, full-fledged neurodegenerative Alzheimer's disease is characterized by severe brain and mental disorders. These include, among others:

• memory
• recall
• language
• faculty of thought and ability to judge
• recognition
• object handling
• orientation.

In the course of the disease, the nature of the human being also changes. Distrust, aggression, restlessness, anxiety, depression, delusions, disinhibition, affect lability or apathy and loss of interest occur across a broad intra- and inter-individual spectrum (7) (8).

1.2.2 Diagnostic possibilities

Adequate biomarkers are suitable for preclinically indicating pathological changes in the brain. From a molecular-biological point of view, a ratio of amyloid-Aβ-1-42 peptides and tau protein from cerebrospinal fluid in the context of imaging techniques such as magnetic resonance imaging (MRI), fluorodeoxyglucose (FDG), positron emission tomography (PET) or the new methods of in-vivo amyloid PET imaging are considered relevant biomarkers in Alzheimer's disease. These are complemented by the immune receptor sTrem2 as an expression of increased activity of the microglia (9). In addition, there are biometric methods for monitoring the progression of neuropsychological disorders.

1.2.3 Therapeutic options

Alzheimer's patients currently have four synthetically produced active ingredients available: the three acetylcholinesterase inhibitors donepezil, rivastigmine and galantamine and the NMDA antagonist memantine. They may delay the decline in mental capacity, alleviate some of the symptoms and slightly improve everyday life skills. Non-drug therapies encompass a range of therapeutic...