Abnormal deposition of misprocessed and aggregated proteins is a common final pathway of most neurodegenerative diseases, including Alzheimer’s disease (AD). AD is characterized by the extraneuronal deposition of the amyloid β (Aβ) protein in the form of plaques and the intraneuronal aggregation of the microtubule-associated protein tau in the form of filaments. Based on the biochemically diverse range of pathological tau proteins, a number of approaches have been proposed to develop new potential therapeutics. Here we discuss some of the most promising ones: inhibition of tau phosphorylation, proteolysis and aggregation, promotion of intra- and extracellular tau clearance, and stabilization of microtubules. We also emphasize the need to achieve a full understanding of the biological roles and post-translational modifications of normal tau, as well as the molecular events responsible for selective neuronal vulnerability to tau pathology and its propagation. It is concluded that answering key questions on the relationship between Aβ and tau pathology should lead to a better understanding of the nature of secondary tauopathies, especially AD, and open new therapeutic targets and strategies.

None of the proposed mechanisms of Alzheimer's disease (AD) fully explains the distribution patterns of the neuropathological changes at the cellular and regional levels, and their clinical correlates. One aspect of this problem lies in the complex genetic, epigenetic, and environmental landscape of AD: early-onset AD is often familial with autosomal dominant inheritance, while the vast majority of AD cases are late-onset, with the ε4 variant of the gene encoding apolipoprotein E (APOE) known to confer a 5-20 fold increased risk with partial penetrance. Mechanisms by which genetic variants and environmental factors influence the development of AD pathological changes, especially neurofibrillary degeneration, are not yet known. Here we review current knowledge of the involvement of the monoaminergic systems in AD. The changes in the serotonergic, noradrenergic, dopaminergic, histaminergic, and melatonergic systems in AD are briefly described. We also summarize the possibilities for monoamine-based treatment in AD. Besides neuropathologic AD criteria that include the noradrenergic locus coeruleus (LC), special emphasis is given to the serotonergic dorsal raphe nucleus (DRN). Both of these brainstem nuclei are among the first to be affected by tau protein abnormalities in the course of sporadic AD, causing behavioral and cognitive symptoms of variable severity. The possibility that most of the tangle-bearing neurons of the LC and DRN may release amyloid β as well as soluble monomeric or oligomeric tau protein trans-synaptically by their diffuse projections to the cerebral cortex emphasizes their selective vulnerability and warrants further investigations of the monoaminergic systems in AD.

Thyroid hormones are necessary for the normal functioning of physiological systems. Therefore, knowledge of any factor (whether genetic, environmental or intrinsic) that alters the levels of thyroid-stimulating hormone (TSH) and thyroid hormones is crucial. Genetic factors contribute up to 65% of interindividual variations in TSH and thyroid hormone levels, but many environmental factors can also affect thyroid function. This review discusses studies that have analyzed the impact of environmental factors on TSH and thyroid hormone levels in healthy adults. We included lifestyle factors (smoking, alcohol consumption, diet and exercise) and pollutants (chemicals and heavy metals). Many inconsistencies in the results have been observed between studies, making it difficult to draw a general conclusion about how a particular environmental factor influences TSH and thyroid hormone levels. However, lifestyle factors that showed the clearest association with TSH and thyroid hormones were smoking, body mass index (BMI) and iodine (micronutrient taken from the diet). Smoking mainly led to a decrease in TSH levels and an increase in triiodothyronine (T3) and thyroxine (T4) levels, while BMI levels were positively correlated with TSH and free T3 levels. Excess iodine led to an increase in TSH levels and a decrease in thyroid hormone levels. Among the pollutants analyzed, most studies observed a decrease in thyroid hormone levels after exposure to perchlorate. Future studies should continue to analyze the impact of environmental factors on thyroid function as they could contribute to understanding the complex background of gene–environment interactions underlying the pathology of thyroid diseases.

Vitamin D is necessary for the normal functioning of many organs, including the thyroid gland. It is, therefore, not surprising that vitamin D deficiency is considered a risk factor for the development of many thyroid disorders, including autoimmune thyroid diseases and thyroid cancer. However, the interaction between vitamin D and thyroid function is still not fully understood. This review discusses studies involving human subjects that (1) compared vitamin D status (primarily determined by serum calcidiol (25-hydroxyvitamin D [25(OH)D]) levels) with thyroid function assessed by thyroid stimulating hormone (TSH), thyroid hormones, and anti-thyroid antibody levels; and (2) evaluated the effect of vitamin D supplementation on thyroid function. Due to the many inconsistencies in the results between the studies, it is still difficult to draw a definite conclusion on how vitamin D status affects thyroid function. Studies in healthy participants observed either a negative correlation or no association between TSH and 25(OH)D levels, while the results for thyroid hormones showed high variability. Many studies have observed a negative association between anti-thyroid antibodies and 25(OH)D levels, but equally many studies have failed to observe such an association. Regarding the studies that examined the effect of vitamin D supplementation on thyroid function, almost all observed a decrease in anti-thyroid antibody levels after vitamin D supplementation. Factors that could contribute to the high variability between the studies are the use of different assays for the measurement of serum 25(OH)D levels and the confounding effects of sex, age, body-mass index, dietary habits, smoking, and the time of year when the samples were collected. In conclusion, additional studies with larger numbers of participants are needed to fully understand the effect of vitamin D on thyroid function.

Background: Neuroinflammation plays an important role in Alzheimer’s disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1 α, IL-1β, IL-6, and tumor necrosis factor α (TNF α) that participate in neuron damage, but also anti-inflammatory cytokines (such as IL-10), which maintain homeostasis of immune response. Previous studies showed the association of IL-1 α –889C/T (rs1800587), IL-1β–1473G/C (rs1143623), IL-6 –174C/G (rs1800795), IL-10 –1082G/A (rs1800896), and TNF α –308A/G (rs1800629) polymorphisms with AD. Objective: We aimed to investigate whether people with certain IL-1 α, IL-1β, IL-6, IL-10, and TNF α genotypes in these polymorphisms are more prone to develop AD-related pathology, reflected by pathological levels of cerebrospinal fluid (CSF) AD biomarkers including amyloid-β _1-42 , total tau (t-tau), tau phosphorylated at Thr 181 (p-tau ₁₈₁ ), Ser 199 (p-tau ₁₉₉ ), and Thr 231 (p-tau ₂₃₁ ), and visinin-like protein 1 (VILIP-1). Methods: The study included 115 AD patients, 53 patients with mild cognitive impairment, and 11 healthy controls. The polymorphisms were determined using real-time polymerase chain reaction. Levels of CSF biomarkers were determined by enzyme-linked immunosorbent assay. Results: A significant increase in p-tau CSF levels was found in patients with the AA IL-10 –1082G/A and GG TNF α –308A/G genotypes, and in carriers of a G allele in IL-1β –1473C/G and IL-6 –174C/G polymorphisms. t-tau levels were increased in carriers of a G allele in IL-1β –1473C/G polymorphism. An increase in VILIP-1 levels was observed in patients with CG and GG IL-1β –1473C/G, GC IL-6 –174C/G, and GG TNF α –308A/G genotype. Conclusion: These results suggest that persons carrying certain genotypes in IL10 (–1082G/A), IL1β (1473C/G), IL6 (–174C/G), and TNFI α (–308A/G) could be more vulnerable to development of neuroinflammation, and consequently of AD.

The default mode network (DMN) is a major resting-state network that supports most of the baseline brain activity. Recent studies revealed that DMN cortical hub regions, including the medial prefrontal cortex, parietal cortex, posterior cingulum, and precuneus are all affected early during Alzheimer’s disease (AD) and exhibit high amounts of Aβ deposits. The cells generating Aβ are chiefly cortical and some brainstem projection neurons. Because processing of the amyloid precursor protein is activity-dependent, it can be speculated that due to their constant activity, DMN neurons produce and release more Aβ than occurs elsewhere in the neocortex, thus leading to an increase in production, oligomerization and aggregation of Aβ as well as tau hyperphosphorylation, which presumably is caused by the released Aβ oligomers. DMN cortical regions are richly innervated by long projection fibers from the noradrenergic locus coeruleus (LC), the serotonergic dorsal raphe nucleus (DRN), as well as the cholinergic basal forebrain (nucleus basalis complex, NB), which all may release high amounts of Aβ in the vicinity of glutamatergic projection neurons in the DMN cortical regions that are vulnerable to tau pathology and neurofibrillary degeneration. Recent findings provide converging evidence that the amyloid accumulation and DMN functional alterations are closely linked with the changes of sleep-wake cycle (particularly in regard of lesser amount of short-wave deep sleep when metabolic demands are about 50% lower in comparison with awake state and when presumably less amyloid is produced) and pre-tangle changes of LC, thus opening new promising area for future research.