Dementia in Alzheimer's: What's Happening?

Macroscopic changes in Alzheimer's disease include diffuse brain atrophy with a decrease in the volume of convolutions and widening of the furrows. With pathohistological examination, patients with Alzheimer's disease are diagnosed with senile plaques, neurofibrillary glomeruli and a decrease in the number of neurons. Similar changes are possible and with normal aging of the brain, but for Alzheimer's disease they are characterized by their quantitative expression and localization, which are of diagnostic significance.

[1], [2], [3], [4], [5]

Cholinergic systems

Alzheimer's disease in the brain disrupts the functioning of the cholinergic systems. A negative correlation was found between the posthumously determined activity of acetylcholinesterase (the enzyme responsible for the synthesis of acetylcholine) and the severity of dementia, determined using special scales shortly before death. Alzheimer's disease marked the selective death of cholinergic neurons. Both in laboratory animals and in humans, a negative effect of anticholinergic agents on the performance of tests evaluating memory has been revealed. At the same time, the use of agents that enhance cholinergic activity led to improved performance of tests in laboratory animals and people with structural changes in the brain or exposed to anticholinergic drugs. The role of the weakening of the activity of cholinergic systems in the pathogenesis of Alzheimer's disease is confirmed by the positive results of clinical trials of inhibitors of cholinesterase, an enzyme that provides metabolic degradation of acetylcholine.

[6], [7], [8], [9], [10], [11]

Adrenergic systems

Neurochemical changes in Alzheimer's disease are complex. Changes in cholinergic activity may be potentiated by dysfunction of other neurotransmitter systems. Clonidine, being an agonist of presynaptic alpha 2-adrenergic receptors, is able to disrupt the function of the frontal cortex. Alpha-2-adrenergic antagonists (eg, idazoxane) increase the release of norepinephrine by blocking presynaptic receptors. Animal studies have shown that cholinesterase inhibitors increase the learning ability, and the blockade of presynaptic alpha 2-adrenergic receptors can potentiate this effect. Thus, an increase in the learning ability of laboratory animals was observed, which was administered a subthreshold dose of acetylcholinesterase inhibitors in combination with alpha2-adrenoreceptor antagonists. Clinical studies of this combination of drugs are currently under way.

[12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24]

Mechanisms of neuronal death

Exciting amino acids

Excitatory amino acids (VAL) can play an important role in the pathogenesis of Alzheimer's disease. It has been established that apoptosis (programmed cell death) can be the result of increased activity of glutamatergic brain systems. High concentrations of glutamate and aspartate are detected in the hippocampus, cortico-cortical and cortico-striatal projections. Activation of glutamate receptors leads to long-term potentiation, which can underlie the formation of traces of memory. Hyperstimulation of these receptors can cause a neurotoxic effect. Three types of ionotropic BAA receptors have been identified: NMDA, AMPA and acetate. NMDA receptors that play an important role in memory and learning processes can be stimulated by glutamate and aspartate, while NMDA itself is a chemical analogue of glutamic acid. The effect of NMDA receptor glutamate stimulation is allosteric modulated by receptor sites interacting with polyamine and glycine. The calcium channel associated with the NMDA receptor is blocked by magnesium ions in a potential-dependent manner. NMDA receptor antagonists, which act only after activation of the receptors, also have a binding site within the ion channel. Laboratory animals show neuroprotective properties of antagonists of both NMDA- and AMPA-receptors.

[25], [26], [27], [28], [29], [30], [31]

Oxidative stress

Oxidation with the formation of free radicals can be responsible, at least in part, for damage to neurons in Alzheimer's disease and other neurodegenerative diseases. It is suggested that the toxic effect of B-amyloid in Alzheimer's disease is mediated by free radicals. Free radical scavengers and other drugs that inhibit the oxidative damage of neurons (for example, immunosuppressors that inhibit the transcription of factors involved in the neurodegenerative process) may play a role in the treatment of Alzheimer's disease in the future.

Calcium

Calcium is a chemical mediator that plays a vital role in the functioning of neurons. Moreover, damage to neurons can be caused by a violation of calcium homeostasis. In studies conducted both in laboratory animals and in humans, it has been shown that nimodipine (but not other calcium channel blockers) is capable of improving memory and learning.

[32], [33], [34], [35], [36], [37], [38], [39]

Inflammation

The participation of inflammatory mechanisms in the pathogenesis of Alzheimer's disease is indicated by epidemiological data, the detection of inflammation factors in neurodegeneration zones, as well as data obtained in vitro and in laboratory animals. Thus, it is established that Alzheimer's disease is less common in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) for a long time, as well as those treated for rheumatoid arthritis. A prospective study in Baltimore, USA, found a lower risk of developing Alzheimer's disease in people taking NSAIDs for more than 2 years, compared to age-matched controls, and the longer they took NSAIDs, the lower the risk of the disease. In addition, surprising pairs of twins with the risk of Alzheimer's disease, the use of NSAIDs reduced the risk of developing the disease and delayed its development.

From the markers of the inflammatory process in the zones of neurodegeneration in Alzheimer's disease, interleukins IL-I and IL-6, activated microglia, Clq (the early component of the complement cascade), and also acute-phase reactants are detected. Studies on tissue cultures in vitro and on laboratory animals confirm the concept that inflammatory factors can participate in the pathogenesis of asthma. For example, in a model of transgenic mice, it was shown that increased production of IL-6 is associated with the development of neurodegeneration, and the toxicity of P-amyloid is enhanced by Clq, which interacts with it and promotes its aggregation. In different cell cultures, IL-2 increases the production of amyloid precursor protein and enhances the toxic effect of P-amyloid 1-42.

Metabolism of amyloid protein

According to the hypothesis of the amyloid cascade proposed by Selkoe, the formation of amyloid is the initiating stage in the pathogenesis of Alzheimer's disease. Neuritic plaques containing amyloid are present in Alzheimer's disease in those areas of the brain that participate in memory processes, and the density of these plaques is proportional to the severity of cognitive impairment. Moreover, the genetic mutations underlying Alzheimer's disease are associated with an increase in production and amyloid deposition. In addition, patients with Down's syndrome, who have been diagnosed with Alzheimer's disease by the age of 50, already have amyloid deposits in their brains at an early age - long before the development of other pathomorphological changes characteristic of Alzheimer's disease. In vitro beta amyloid damages neurons, activates microglia and inflammatory processes, and blockade of P-amyloid formation prevents toxic effects. In transgenic mice transplanted with the mutant human amyloid precursor protein gene, many of the pathomorphological signs of Alzheimer's disease develop. From the pharmacological point of view, the initial stage of the amyloid cascade is a potential target for therapeutic intervention in Alzheimer's disease.

Metabolism of tau protein

Neurofibrillary glomeruli are another characteristic pathogistological marker of Alzheimer's disease, but they also occur in a number of other neurodegenerative diseases. The glomeruli consist of paired filaments formed as a result of pathological aggregation of tau protein. Mostly they are found in axons. Pathological phosphorylation of tau protein can disrupt the stability of the microtubule system and participate in the formation of glomeruli. Phosphorylated tau protein is detected in the hippocampus, parietal and frontal cortex, that is, in those zones that are affected by Alzheimer's disease. Means that affect the metabolism of tau protein can protect neurons from the destruction associated with the formation of glomeruli.

Genetics and molecular biology

The development of some cases of Alzheimer's disease is associated with mutations in the genes encoding presenilin-1, presenilin-2 and the amyloid precursor protein. Other genotypes, for example, APOE-e4, are associated with an increased risk of Alzheimer's disease. There are three alleles of the gene apolipoprotein E (APOE), located on the 19 th chromosome: APOE-e2, APOE-e3 and APOE-e4. Allele APOE-e4 with an increased frequency is detected in elderly people placed in care institutions. In some studies, the presence of the APOE-e4 allele in patients with late-onset Alzheimer's disease was associated with an increased risk of developing the disease, an earlier age of death, and a more severe course of the disease, but other researchers did not confirm this data.