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Early diagnosis of Alzheimer's disease (AD) is of great practical importance. The process of differentiating a disease with symptoms of dementia caused by another pathology of the nervous system is based on a subjective assessment. The pathogenesis of AD emphasizes the importance of neuropil beta-amyloid deposition in the brain and the tau protein inside neurons, which is found 20 years before the onset of clinical symptoms of the disease. The number of people suffering from AD doubles every 20 years and in 2050 there will be 115.4 million of them worldwide. The level of education and constant intellectual activity may be a factor protecting against the occurrence of AD. The diagnosis of AD takes into account information obtained from interviews as well as from additional imaging and laboratory tests. The available criteria for AD diagnosis are constantly modified and changed, which makes their application in everyday practice difficult., (© 2022 MEDPRESS.)

The characteristic hallmark of Alzheimer's disease (AD) are progressive changes in the brain structure and function, caused by aggregation of senile plagues, composed of improperly folded amyloid β(Aβ) protein, in the brain tissue. Recent research has suggested that causes of AD are closely associated with perturbation on the molecular level caused by the activation of the pro-apoptotic, PERKdependent Unfolded Protein Response (UPR) signaling pathway activated under Endoplasmic Reticulum (ER) stress conditions., Aim: The aims of the study were evaluation of the activity of the smallmolecule inhibitors of PERK kinase, GSK2606414 and LDN-0060609, via the analysis of the level of the phosphorylation of eIF2α as one of the main markers of the UPR signaling pathway activation as well as evaluation of the cytotoxicity of the inhibitor LDN-0060609., Materials and Methods: The study was conducted on commercially available cell lines of wild type mouse embryotic fibroblasts 3T3 MEFs WT and with deletion of PERK gene 3T3 MEFs KO, mouse neurons CATH.a and human neuroblastoma SH-SY5Y with overexpression of amyloid precursor protein (APP). Cells were treated with commercially available inhibitor GSK2606414 or LDN-0060609, selected from the small-molecule compounds library Laboratory for Drug Discovery in Neurodegeneration, on appropriate cell culture medium with thapsigargin as an activator of Endoplasmic Reticulum (ER) stress conditions. To evaluate the level of eIF2α phosphorylation we used the Western blot technique. Detection of immune complexes was performed using the chemiluminescence. Evaluation of the LDN-0060609 compound cytotoxicity was carried out on SH-SY5Y cells using the XTT assay., Results: The results of the study showed that the commercially available GSK2606414 inhibitor at a concentration of 1 μM causes >85% inhibition of the phosphorylation of eIF2α in all tested cell lines. The newly tested LDN-0060609 inhibitor showed the highest inhibitory activity at 25 μM resulting in 52% inhibition of eIF2α phosphorylation. In addition, the LDN-0060609 inhibitor did not induce a cytotoxic effect at any used concentrations and incubation times. Conclusions. It is believed that the LDN-0060609., Conclusions: It is believed that the LDN-0060609 inhibitor, that in comparison with commercially available GSK2606414 inhibitor does not evoke a cytotoxic effect, may constitute a potential factor inhibiting activation of the PERK-dependent UPR signaling pathway responsible for neurodegenerative processes in AD. Small-molecule PERK inhibitors may constitute an innovative therapeutic strategy for AD treatment., (© 2019 MEDPRESS.)

Selective drugs directed at a single biological target often prove ineffective in the treatment of diseases with a complex pathomechanism, e.g. Alzheimer's disease (AD). This situation prompts researchers to design multi-target-directed ligands (MTDLs), capable of interacting with a number of selected biological targets. The paper outlines the concept of the multi-target-directed ligand design and examples of its use in the search of a cure for AD. In the knowledge-based approach for designing MTDLs, selective ligands of different targets are combined in one molecule. In the screening-based approach, libraries of compounds are screened against selected targets, which allows one to find molecules with a desirable pharmacological profile. It is also possible to obtain multifunctional ligands by performing optimization of a drug with known side activity and transforming it into the main activity, with a simultaneous decrease or complete removal of the original activity. The type of biological targets and applied MTDL design strategy affect the physicochemical and pharmacokinetic properties of the resulting molecules. AD is a multifactorial neurodegenerative disease of the central nervous system associated with the formation of neurofibrillary tangles within neurons, formed by the hyperphosphorylated τ proteins, and extracellular β-amyloid deposits (senile plaques). Current AD therapy comprises symptomatic drugs that enhance cholinergic neurotransmission or inhibit glutamate receptors. The literature provides numerous examples of compounds which proved in in vitro tests to be multifunctional ligands. Most of them are derivatives of cholinesterase-inhibiting drugs, also capable of inhibiting the aggregation of Aβ and showing neuroprotective effects in Aβ-induced cytotoxicity assays.

Recently published data demonstrated that increased release, oligomerization and toxicity of α-synuclein (ASN) is a key molecular process in pathophysiology of neurodegenerative diseases classified as synucleinopathies (e.g. Parkinson disease or Alzheimer's disease). It was proved that the excessive release of ASN into the extracellular space, driven by environmental factors as well as neurodegeneration, may have a significant role in the spread of the neurodegeneration process within the brain. Extracellular ASN was shown to be toxic both to neurons and glial cells and the mechanism of its action depends on the concentration of this protein in the extracellular space. Exogenous ASN leads to the activation of plasma membrane receptors, causes increased calcium influx, and stimulates the synthesis of proinflammatory cytokines and nitric oxide, which in turn leads to activation of programmed cell death. These data provide new insights into the involvement of ASN in the neurodegenerative diseases, and thus can serve effectively for the development of their new therapy.

Ceramides, members of the sphingolipids, are produced in the central nervous system by de novo synthesis, sphingomyelin hydrolysis or the so-called salvage pathway. They are engaged in formation of lipid rafts that are essential in regulation and transduction of signals coming to the cell from the environment. Ceramides represent the major transmitters of the sphingomyelin pathway of signal transduction. They regulate proliferation, differentiation, programmed cell death and senescence. Ceramide overexpression, mainly as a result of sphingomyelin hydrolysis, is a component of brain damage caused by ischemia and early reperfusion. Their high concentrations induce mitochondria-dependent neuronal apoptosis, exacerbate the synthesis of reactive oxygen species, decrease ATP level, inhibit electron transport and release cytochrome c, and activate caspase-3. Reduced ceramide accumulation in the brain, dependent mainly on ceramide synthesized de novo, may exert an anti-apoptotic effect after pre-conditioning. The increase of ceramide content in the brain was observed in Alzheimer disease and its animal models. Enhanced ceramide concentration in this pathology is an effect of their synthesis de novo or sphingomyelin metabolism augmentation. The ceramide pathway can directly stimulate biochemical changes in the brain noted at the onset of disease: tau overphosphorylation and β-amyloid peptide accumulation. The higher concentration of ceramides in blood in the pre-clinical phase of the illness may mark early brain changes.

All neurodegenerative diseases are related to pathology and accumulation of proteins. Proteins are basic structural and functional components of each cell and their functions are associated with their amino acid composition and spatial structure. The proper functioning of protein is necessary for the proper operation of the body system. In the case of disorders of proteins' spatial structure, the development of pathological processes may occur. Accumulation of abnormal proteins is toxic to nerve cells and causes neurodegeneration. Different disorders are characterized by abnormalities of various proteins. This type of neurodegenerative diseases includes Parkinson's disease, tauopathies, Alzheimer's disease, and prion diseases. Parkinson's disease is characterized by toxicity of α-synuclein. The pathology of tau protein is specific for tauopathies, prion protein for prion diseases. In the case of Alzheimer's disease it is β-amyloid. All proteins responsible for the pathology are present in the physiological state in the organism. Damage to the area of the brain covered by the pathological process and the clinical symptoms are characteristic for a particular type of disease. Detailed knowledge of the mechanisms of the disease can be an important element in the development of effective ways of treatment.

Recognition of pathogens by innate immune cells is mediated by pattern recognition receptors (PRR), which include scavenger receptors (SR). The class A SR, SR-A/CD204 and MARCO, are characterized by the presence of collagenous and SR cysteine-rich domains in their extracellular portions. Both receptors are expressed mainly on macrophages and dendritic cells. Thanks to their ability to bind to a wide range of polyanionic ligands, the class A SR may participate in numerous functions of these cells, such as endocytosis, and adhesion to extracellular matrix and to other cells. Among SR-A ligands are oxidized lipoproteins and β-amyloid fibrils, which link SR-A to the pathogenesis of arteriosclerosis and Alzheimer's disease. Despite the demonstration of class A SR involvement in so many processes, the lack of selective ligands precluded reaching definite conclusions concerning their signaling abilities. Using specific receptor ligation with antibodies, we showed that SR-A and MARCO trigger intracellular signaling, modulating pro-inflammatory and microbicidal activities of macrophages. Surprisingly, despite similarities in structure and ligand binding repertoires, SR-A and MARCO exert opposite effects on interleukin-12 (IL-12) production in macrophages. SR-A ligation also stimulated H₂O₂ and IL-10 production, but had no effect on the release of several other cytokines. These limited effects of specific SR-A ligation contrast with generalized enhancement of immune responses observed in SR-A-deficient mice. Recent studies have revealed that many of these effects of SR-A deficiency may be caused by compensatory changes in the expression of other receptors and/or disinhibition of signal transduction from receptors belonging to the Toll/IL-1R family, rather than by the loss of the receptor function of SR-A.

Forty years after Singer and Nicolson (1972) announced the fluid mosaic membrane model a number of new facts caused updating of their historic view. Plasma membrane is not uniform in state of matter, i.e. fluid portion is represented by glycerophospholipids spontaneously mounted into lipid bilayer in disordered manner (Ld - liquid disordered). In such membrane numerous nanodomains (millions in single cell) known as lipid rafts (TL) and caveolae contain sphingolipids and cholesterol as well as lipid modified integral membrane proteins. Nanodomains are more rigid, denser portion of plasma membrane (Lo - liquid ordered). Nanodomains are buoyant in fluid portion of membrane and have tendency to coalesce into larger platforms to form signalosomes essential for signal transduction. TL constitutively express certain proteins (alpha subunits of heterotrimeric G proteins, secretases, caveolins, flotillin). There are other proteins found in TL after additional lipid modifications (palmitoylation, myristoylation). With regard to dementia, retrospective studies carried out in human beings point to cholesterol and TL as crucial factors in etiopathogenesis of Alzheimer's disease (AD). Chronic administration of statins to patients significantly reduced the incidence of AD. This article is intended to make closer view into the molecular basis of AD and sheds more light on possible causal links between TL and AD.

The trafficking of proteins in the secretory pathway is mediated by vesicles. Proteins of the p24 family are present on the membranes of secretory pathway organelles (ER, Golgi, COPI and COPII vesicles). Evidence exists showing that p24 proteins play a role in the development of Alzheimer disease, making them an interesting research subject. Their presence in the secretory pathway and their tissue-dependent expression levels suggest that p24 proteins are involved in secretion. However, their molecular function is not clear. Several potential functions have been proposed for p24 proteins: (1) that they function as receptors for selected cargo; (2) that they regulate vesicle biogenesis; (3) that they perform structural and morphogenetic functions in the secretory pathway; (4) that they are responsible for quality control of transported proteins. In this article, we provide a critical review of the postulated functions of p24 proteins.

In the course of Alzheimer's disease (AD), chronic inflammation is initiated by amyloid beta (Ab) peptide aggregates that extensively participate in neurodegeneration. Epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD. NSAIDs are inhibitors of cyclooxygenases (COXs), enzymes involved in synthesis of eicosanoids, a major component of the inflammatory process. Recent studies have brought two new findings: 1) the toxic form of Ab is its intra- and extracellular oligomers, rather than aggregates; 2) COX-2 activation is an early event in AD, preceding plaque formation and microglia activation. This finding suggests that COX might participate in Ab toxicity in neurons in the early stage of AD independently of its role in the inflammatory reaction in glial cells in the advanced stage of AD. However, further studies on the role of COXs in the pathogenesis/pathomechanism of AD are needed.

Ketogenic diet has been used in treating epilepsy for more than 80 years. It is based on a drastic change of proportions in the consumption of carbohydrates, proteins and fats. In everyday diet we consume approximately 34 per cent of fats, 50 per cent of carbohydrates and 14 per cent of proteins. While ketogenic diet consists in 80-90 per cent of fats and in 10-20 per cents of carbohydrates and proteins together. Despite its indisputable effectiveness, the functioning of the ketogenic diet has not been explained. It seems that its functioning mechanism is unique and results from a number of chronic metabolic changes as well as the adaptation in the cenral nervous system that occurs during its long-term application. The most recent clinical and experimental data suggest that the ketogenic diet also has neuroprotective properties, which makes it a useful alternative therapeutic method in the modification of the natural history of the diseases related with neurodegeneration processes.

Neurodegenerative diseases (e.g., Alzheimer's Disease, Parkinson's Disease and Amyotrophic Lateral Sclerosis), are characterized by the deposition of misfolded proteins (alpha beta-peptide, alpha-synucleine and Cu, Zn superoxide dismutase, respectively). Oxidative stress is accompanied by the diminished level of catecholamines in neuronal tissue. Beside their role in transduction of nervous stimuli, catecholamines might act as antioxidants. Herein, we focused on the antioxidant activity of catecholamine neurotransmitters--dopamine (and its precursor L-DOPA), adrenaline and noradrenaline. There is an increasing evidence that catecholamines might act as scavengers of free radicals and experimental data indicate the antioxidant potency of catecholamines. However, the exact mechanism of this action is not defined.

Neprilysin (NEP, CD10, CALLA-common acute lymphoblastic leukaemia antigen, neutral endopeptidase, enkephalinase) is a zinc-dependent metallopeptidase, which is involved in the metabolism of a number of regulatory peptides and plays an important role in turning off peptide signalling at the cell surface. Neprilysin is involved in many physiological and pathological processes in organism. It regulates blood pressure and inflammatory response, takes part in the pathogenesis of Alzheimer disease, influences cellular proliferation and differentiation, as well as neoplastic progression.

Aim: The relationship between genetically determined polymorphic oxidation and acetylation and susceptibility to some disease has aroused much interest. The aim of our study was to evaluate whether patients with Alzheimer's disease differ from healthy persons in their ability to oxidize sparteine and acetylate sulphadimidine as model substance., Method: Oxidation and acetylation phenotype were estimated in 20 patients with Alzheimer's disease. The control group consisted of 160 healthy volunteers for comparison of oxidation phenotype and 45 healthy subjects for comparison of acetylation phenotype., Results: The phenotyping of oxidation revealed two distinct populations among 20 patients with Alzheimer's disease: 19 persons (95%) were extensive metabolizers (EMs) of sparteine and 1 person (5%) was a poor metabolizer (PMs). In 160 healthy persons, 146 persons (91.2%) were extensive metabolizers of sparteine and 14 persons (8.8%) were poor metabolizers. The difference between the frequency distribution of PMs and EMs in healthy persons and in patients with Alzheimer's disease was not statistically significant. The phenotyping of acetylation showed that among 20 patients with Alzheimer's disease 10 persons (50%) were rapid acetylators and 10 persons (50%) were slow acetylators. In 45 healthy subjects the phenotype of rapid acetylation was observed in 23 persons (5 1%) and slow acetylation in 22 persons (49%). Our study showed a lack of statistically significant differences between the percentage of rapid acetylators (51%) and of slow acetylators (49%) in the control group of healthy volunteers and in the group ofAlzheimer's disease., Conclusion: The results of our study may suggest that phenotypes of oxidation and acetylation are not associated with risk of the development of Alzheimer's disease.

Alzheimer's disease (AD) is a very common progressive neurodegenerative disorder. AD patients are affected by cognitive and memory deterioration. Cerebral degeneration, with selective neuronal death induced by extracellular amyloid deposits in the form of senile plaques and intracellular neurofibrillary tangles composed of helical paired tau protein, is the best-studied pathological event related to AD. Presenilins and apolipoprotein E are other neurotoxic agents involved in the pathogenesis of AD. A large body evidence has shown that permanent activation of glial cells in the brains of AD patients promotes the production of excessive quantities of free radicals, nitric oxide, and cytokines which could be detrimental to neuronal cells. Damage to the blood-brain barrier by inflammatory processes result in the influx of peripheral immune system cells and local immune reactions. Inhibition of ROS and NO overproduction as well as endogenic regulation of cytokine induction could be of therapeutic importance and delay neurodegeneration in AD.

Alzheimer's disease is a complex neurodegenerative disorder. Several risk factors have been reported and compiled from genetic and epidemiological studies. Many theories on the cause of Alzheimer's disease have been proposed over the past. Amyloid hypothesis is still the most important one and guides a lot of scientific research on AD. But there is general consent that amyloid deposits are the products of degenerating neurons, not a cause of degeneration. Recently, epidemiological data for the correlation between HSV-1 infection and AD have been collected. It was revealed that HSV-1 is present in a latent form in the brains of a high proportion of elderly people and is a risk factor for AD in carriers of APOEepsilon4. On the other hand, there is negative evidence for HSV-1 as a risk factor of APOEepsilon4 positive AD cases. Finally, some investigations raise a possibility that viruses other than HSV-1 may influence Alzheimer's disease. In the present paper the possible role of HSV-1 infection in pathology of AD is discussed.

Lactoferrin (LF) is a protein secreted by the tissues of ectodermal origin. Its structure is similar to transferrin. LF appeared to be multifunctional, but its main functions are connected with the natural defense system of mammals. The biological role and origin of LF within brain in normal and disease processes are as yet uncharted. LF expression is greatly upregulated during neurodegenerative disorders and in elderly brains. LF may exert an antiinflammatory function via its inhibitory effect on hydroxyl radical formation. By antioxydative properties, LF prevents DNA damage and consequently tumor formation in the CNS. Moreover, LF specifically transactivates the p53 tumor suppressor gene. LF suppresses distress perception via opioid mediated mechanism and prevents a decrease of the immune system activity caused by psychosocial stress. Furthermore, LF possibly modulates behavior in man and in animals.

The paper presents current opinions on the mechanism of beta-amyloid accumulation, the role of cholesterol in the pathogenesis of dementia and observations of the role of statins in its development. Most of the observations were done on Alzheimer's disease, some of them concerned also dementia of a vascular origin and cognition. Statins are inhibitors of the cholesterol synthesis pathway. The mechanism of their action concerns not only their influence on the cholesterol level but also their influence on prenylation of various proteins and in consequence inhibition of inflammatory reactions. They exert also antioxidative activity. As the number of prospective studies is still insufficient the question whether statins could be used as drugs against dementia remains still unsolved.

Alzheimer's disease is associated with the formation of extracellular senile plaques and intracellular neurofibrillary tangles. In the neurons of patients, all the morphological features of apoptosis, e.g. blebbing, formation of apoptotic bodies, and chromatin condensation, as well as cytoskeleton reorganization were observed. Actin filaments interact with proteins characteristic of Alzheimer's disease, such as apolipoprotein E, amyloid precursor protein, pressenilin, and tau protein. The degeneration of neurons is associated with the formation of Hirano bodies, which contain actin, cofilin, tubulin, tau protein, and proteins of the MAP family and APP. Actin rods are also observed in postmortal brains of patients with Alzheimer's disease. These 'rods' have been shown to play a role in Hirano body precursors.

According to the beta-amyloid cascade hypothesis, the accumulation of beta-amyloid (Abeta) deposits as amyloid plaques in the patient's brain is the primary event in the pathogenesis of Alzheimer's disease (AD). Other neuropathological changes such as neurofibrillary tangles (NFTs), synaptic degeneration and neuronal cell loss are secondary and appear as a consequence of Abeta deposition. Abeta is generated during the proteolytic processing of the beta-amyloid precursor protein (APP). The endoproteolysis of APP is catalyzed by alpha-, beta-, and gamma-secretases. The alpha-secretase pathway releases non-amyloidogenic products: sAPPbeta, p3 and C83 peptides. In the beta-secretase pathway, apart from the sAPPalpha and C99 fragments also beta-amyloid peptides: Abeta40 and/or Abeta42 are generated. Abeta42 is neurotoxic and more hydrophobic than Abeta40, thus it has stronger tendency to oligomerize and aggregate. The imbalance between Abeta production and Abeta clearance is the basis for the formation of amyloid plaques. The majority of known APP and presenilin mutations responsible for familial early onset AD affect APP processing causing overproduction of Abeta, especially Abeta42. Both extracellular and intracellular accumulation of Abeta initiates a cascade of the following events leading to the neurodegeneration: synaptic and neuritic injury, microglial and astrocytic activation (inflammatory response), altered neuronal ionic homeostasis, oxidative damages, changes of kinases/phosphatases activities, formation of NFTs, and finally cell death. In this paper, we reviewed recent findings supporting the presented hypothesis.

Recent studies suggest that apart from nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is another inorganic gaseous mediator in the cardiovascular system. H2S is synthesized from L-cysteine by either cystathionine beta-synthase (CBS) or cystathionin gamma--lyase (CSE), both using pyridoxal 5'-phosphate (vitamin B6) as a cofactor. CBS is the main H2S-producing enzyme in the brain and CSE is involved in H2S formation in the cardiovascular system. H2S induces hypotension in vivo and vasodilation vitro by opening KATP channels in vascular smooth muscle cells. Chronic administration of CSE inhibitor induces arterial hypertension in the rat. In addition, decreased H2S generation has been demonstrated in the vasculature of spontaneously hypertensive rat, in experimental hypertension induced by NO synthase blockade, and in hypoxia-induced pulmonary hypertension, and administration of exogenous H2S donor has significant therapeutic effects in these models. Deficiency of H2S may contribute to atherogenesis in some patients with hyperhomocysteinemia, in whom the metabolism of homocysteine to cysteine and H2S is compromised by vitamin B6 deficiency. Reduced H2S production in the brain was observed in patients with Alzheimer's disease. On the other hand, excess of H2S may lead to mental retardation in patients with Down's syndrome and may be involved in the pathogenesis of hypotension associated with septic shock.

Advanced glycation end-products (AGEs) are formed during non-enzymatic glycation--the process occurring in vitro and in the organism. The glycation products accumulate in tissues and interact with specific receptors, what induces various cellular responses. Some enzymes important in metabolism can be also glycated. The disturbances of homeostasis, related to the glycation products, are the reason for complications observed in diabetes and aging processes. There are presented in this paper: mechanism of the formation of AGEs, their cellular receptor (RAGE), as well as the effects of glycation in aging, diabetes and Alzheimer disease. Finally, there are described the compounds which could be useful as inhibitors of glycation in clinical practice.

Advancement in research on glication process in pathogenesis of AD is presented. Its results may open new, promising possibilities of treatment of neurodegenerative diseases including AD with inhibitors of glication.

In CT images the atrophy of medial parts of temporal lobes was evaluated in 60 patients with Alzheimer-type dementia. In the genotype of 30 patients at least one APOE epsilon 4 allele was identified, the other 30 patients served as the control group. The results of in vivo measurements of temporal lobe atrophy in the examined patients did not show statistically significant relations with APOE genotype which was probably due to entirely different nature and application of both tests.

The paper discusses therapeutical approaches to Alzheimer's disease on the basis of pathological mechanisms responsible for neurodegeneration. Amyloid plaques called also senile plaques situated extracellularly cause loss of neurons, especially cholinergic neurons, that begin in Nucleus of Meynert. However, recent evidence from postmortem brain and fibroblast studies suggests that both adenylyl cyclase and phosphatidylinositol hydrolysis signal transduction cascades are disrupted in AD. Such disruption may limit cholinergic pharmacotherapy. Other disorders, like disturbances in releasing Neuronal Growth Factor (NGF), oxidative stress, free Ca 2+, neuroimmunologic reactions are also important in AD brain changer. Only use of acetylcholine inhibitors: tacrine, donepezil and Gingko Biloba as well as nimodipine improved mental functions (MMSE screening). Neuroprotection of selegiline and NGF was observed. Behavioral symptoms often associated with dementia, like depression, anxiety, irritability, delusions, aggressiveness were treated with: olazepine, risperidone, haloperidol, clozapine, fluoxetine, paroxetine, sertraline, trazodon, dezypramine, lithium, benzodiazepines, carbamazepine and valproic acid. Drugs with strong anticholinergic effects, such as amitriptyline or imipramine should not be administered. Future studies on therapy to regulate metabolism of amyloid precursor-beta-APP are necessary to discover new efficient strategies.

A new family of presenilin genes involved in the pathogenesis of early-onset autosomal dominant Alzheimer's disease (AD) has been identified recently. Mutations in presenilin-1 and presenilin-2 genes have a full penetration and lead to AD. The presenilins are transmembrane proteins localized mainly within endoplasmatic reticulum and Golgi systems. Their biological function remains unknown. It has been suggested that the presenilins may be important for intracellular processes of protein trafficking and processing. Presenilin mutations play a direct role in the beta-amyloid precursor protein metabolism and cause increased production of amyloidogenic A beta 42(43) peptide.

The concentrations were determined of triglycerides (TG), total cholesterol (Ch), high density fraction of (HDL-Ch), low density fraction of cholesterol (LDL-Ch), apolipoprotein B (apo-B) in patients with dementia of Alzheimer type (DAT, 14 patients) and multi-infarct dementia (MID, 63 patients). No significant differences in the estimated lipid parameters in both groups were found, except the calculated value of atherogenic index (Ch/HDL-Ch), which was significantly higher in patients with MID. Our results suggest that this parameter is a much more sensitive atherogenic indicator in blood-vessels than other tested lipid parameters. This finding may influence the therapeutic approach to patients with dementia.