First unified time-course of Alzheimer's-like pathology in the intracerebroventricular streptozotocin-rat model: A systematic review.

Alzheimer's disease and related dementias: From risk factors to disease pathogenesis.

During the past 2 decades, the elucidation of susceptibility and causative genes for Alzheimer disease as well as proteins involved in the pathogenic process has greatly facilitated the development of genetically altered mouse models. These models have played a major role in defining critical disease-related mechanisms and in evaluating novel therapeutic approaches, with many treatments currently in clinical trial owing their origins to studies initially performed in mice. This review discusses the utility of transgenic mice as a research tool and their contributions to our understanding of Alzheimer disease.

Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids

In Alzheimer disease (AD) and frontotemporal dementia the microtubule-associated protein Tau becomes progressively hyperphosphorylated, eventually forming aggregates. However, how Tau dysfunction is associated with functional impairment is only partly understood, especially at early stages when Tau is mislocalized but has not yet formed aggregates. Impaired axonal transport has been proposed as a potential pathomechanism, based on cellular Tau models and Tau transgenic mice. We recently reported K369I mutant Tau transgenic K3 mice with axonal transport defects that suggested a cargo-selective impairment of kinesin-driven anterograde transport by Tau. Here, we show that kinesin motor complex formation is disturbed in the K3 mice. We show that under pathological conditions hyperphosphorylated Tau interacts with c-Jun N-terminal kinase- interacting protein 1 (JIP1), which is associated with the kinesin motor protein complex. As a result, transport of JIP1 into the axon is impaired, causing JIP1 to accumulate in the cell body. Because we found trapping of JIP1 and a pathological Tau/JIP1 interaction also in AD brain, this may have pathomechanistic implications in diseases with a Tau pathology. This is supported by JIP1 sequestration in the cell body of Tau-transfected primary neuronal cultures. The pathological Tau/JIP1 interaction requires phosphorylation of Tau, and Tau competes with the physiological binding of JIP1 to kinesin light chain. Because JIP1 is involved in regulating cargo binding to kinesin motors, our findings may, at least in part, explain how hyperphosphorylated Tau mediates impaired axonal transport in AD and frontotemporal dementia.

Cholesterol is essential for neuronal physiology, both during development and in the adult life: as a major component of cell membranes and precursor of steroid hormones, it contributes to the regulation of ion permeability, cell shape, cell-cell interaction, and transmembrane signaling. Consistently, hereditary diseases with mutations in cholesterol-related genes result in impaired brain function during early life. In addition, defects in brain cholesterol metabolism may contribute to neurological syndromes, such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), and even to the cognitive deficits typical of the old age. In these cases, brain cholesterol defects may be secondary to disease-causing elements and contribute to the functional deficits by altering synaptic functions. In the first part of this review, we will describe hereditary and non-hereditary causes of cholesterol dyshomeostasis and the relationship to brain diseases. In the second part, we will focus on the mechanisms by which perturbation of cholesterol metabolism can affect synaptic function.

The goal of this study was to examine the neuroprotective effect of ebselen against intracerebroventricular streptozotocin (ICV-STZ)-induced oxidative stress and neuronal apoptosis in rat brain. A total of 30 adult male Sprague-Dawley rats were randomly divided into 3 groups of 10 animals each: control, ICV-STZ, and ICV-STZ treated with ebselen. The ICV-STZ group rats were injected bilaterally with ICV-STZ (3 mg/kg) on days 1 and 3, and ebselen (10 mg/kg/day) was administered for 14 days starting from 1st day of ICV-STZ injection to day 14. Rats were killed at the end of the study and brain tissues were removed for biochemical and histopathological investigation. Our results demonstrated, for the first time, the neuroprotective effect of ebselen on Alzheimer's disease (AD) model in rats. Our present study, in ICV-STZ group, showed significant increase in tissue malondialdehyde levels and significant decrease in enzymatic antioxidants superoxide dismutase and glutathione peroxidase in the frontal cortex tissue. The histopathological studies in the brain of rats also supported that ebselen markedly reduced the ICV-STZ-induced histopathological changes and well preserved the normal histological architecture of the frontal cortex tissue. The number of apoptotic neurons was increased in frontal cortex tissue after ICV-STZ administration. Treatment of ebselen markedly reduced the number of degenerating apoptotic neurons. The study demonstrates the effectiveness of ebselen, as a powerful antioxidant, in preventing the oxidative damage and morphological changes caused by ICV-STZ in rats. Thus, ebselen may have a therapeutic value for the treatment of AD.

Moving Beyond Amyloid in Alzheimer's Therapeutics

Tau Pathology Generated by Overexpression of Tau

COVID-19, perioperative neurocognitive disorder and SARS-CoV-2-induced dysregulation of the renin–angiotensin system and kynurenine metabolism. Comment on Br J Anaesth 2021; 127: e113–e115

Chronic treatment with trans resveratrol prevents intracerebroventricular streptozotocin induced cognitive impairment and oxidative stress in rats

Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

Accelerated Human Mutant Tau Aggregation by Knocking Out Murine Tau in a Transgenic Mouse Model

Amyloid Activates GSK-3β to Aggravate Neuronal Tauopathy in Bigenic Mice

The etiology of Alzheimer’s disease (AD) remains a great challenge for neurological research. Extensive investigations for almost one hundred years have led to profound insights of the pathological and molecular mechanisms that affect the AD brain, and there are several hypotheses about what causes the characteristic AD related dementia. The focus has fallen increasingly on the deposition of s-amyloid (As) in the cortex and it is believed, that the generation and deposition of As is the leading cause of the disruptions observed in the AD brain. As has been shown to provoke neuron death, decreased synaptic plasticity, aberrant sprouting of growing axons, chronic inflammation and hyper-phosphorylation of tau. In recent years, research on adult neurogenesis in the mammalian brain has led to surprising findings: new neurons are added daily to specific regions of the brain and growing evidence suggests that these new neurons play a critical role for learning and memory, mood and, to a limited amount, repair of damaged cortical areas. All of these functionalities of neurogenesis are affected in AD patients and the question must be raised, if in the AD brain, neurogenesis is directly disturbed. Defects in neural stem cell biology might significantly contribute to AD dementia and the examination of the relationship of AD lesions and neural stem cell biology might provide new insights for the understanding and treatment of AD. Only recently has it become possible to investigate neural stem cell biology in the AD brain. This is partly because only recent findings revealed the function of adult neural stem cells, but also because animal models for AD have only been available for few years. However, most AD mouse models, which are genetically engineered for As deposition, do not develop significant amyloid plaques until past their median lifespan. This limits their availability and the specificity to As is reduced due to accompanying age effects. In a first study of this thesis, age related changes of neurogenesis were investigated by monitoring the progressive stages of hippocampal neurogenesis: proliferation, survival and differentiation, in four different age groups of wild type C57BL/6J mice. Net-neurogenesis was rapidly reduced in adult compared to young mice, but remained stable at a low level in aged and senescent mice. This effect could be attributed mostly to an age related decline of proliferation with a concomitant increase of survival rates in aged mice. These results suggest that neurogenesis in aged mice remains as functional as in adult mice, although the plasticity of the neurogenic system appears to be reduced compared to young mice. The finding that a reduced caloric diet, a treatment known to reduce age related defects, did not have an effect on neurogenesis confirmed the finding that neurogenesis is not impaired in aged mice compared to adult mice. In a second study neurogenesis was studied in APP23 mice, a transgenic AD mouse model with progressive amyloid plaque load. Adult As pre-depositing and aged As high-depositing mice were investigated. Surprisingly, aged APP23 mice showed an increased number of new neurons in the hippocampus compared to age matching controls. For a closer investigation of the interaction of neural stem cells and As, we crossed mice expressing GFP under a stem cell specific promoter with a new AD mouse model with cortical plaque deposition in early adulthood. Stem cells were reduced in numbers, strongly attracted to As and morphologically altered. In addition, the population of more differentiated immature neurons appeared to be morphologically unaffected by As. These findings show that As affects neural stem cell biology concomitant with an up-regulation of neurogenesis. Several reports claim that stem cells from the periphery are able to cross the blood brain barrier and are able trans-differentiate to the neuronal lineage. It has also been shown, that the number of cells immigrating from the periphery increases in AD mouse models. Thus, in a third study we investigated if stem cells from the peripheral hematopoietic system could participate in the repair or replacement of the damaged neuronal tissue. APP23 mice were deprived of their immune system by gamma irradiation and later reconstituted with genetically marked hematopoietic stem cells. We found a large number of these cells invading the brains of aged APP23 mice, but cell fate analysis revealed that these cells matured to macrophages or T-cells, but none differentiated towards the neuronal lineage. We conclude that the hematopoietic system is involved in the immune response in the brain, but we found no evidence that it is involved the in repair of the damaged network or in the alterations of neural stem cell biology described above. In conclusion, the results of the present thesis provide evidence of a defective behavior of neural stem cells in the amyloidogenic brain, but also unveil the limitations in the function and ability of neural stem cells in the aged brain.

Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are severe age-related disorders with complex and multifactorial causes. Recent research suggests a critical link between neurodegeneration and the gut microbiome, via the gut–brain communication pathway. This review examines the role of trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, in the development of AD and PD, and investigates its interaction with microRNAs (miRNAs) along this bidirectional pathway. TMAO, which is produced from dietary metabolites like choline and carnitine, has been linked to increased neuroinflammation, protein misfolding, and cognitive decline. In AD, elevated TMAO levels are associated with amyloid-beta and tau pathologies, blood–brain barrier disruption, and neuronal death. TMAO can cross the blood–brain barrier and promote the aggregation of amyloid and tau proteins. Similarly, TMAO affects alpha-synuclein conformation and aggregation, a hallmark of PD. TMAO also activates pro-inflammatory pathways such as NF-kB signaling, exacerbating neuroinflammation further. Moreover, TMAO modulates the expression of various miRNAs that are involved in neurodegenerative processes. Thus, the gut microbiome–miRNA–brain axis represents a newly discovered mechanistic link between gut dysbiosis and neurodegeneration. MiRNAs regulate the key pathways involved in neuroinflammation, oxidative stress, and neuronal death, contributing to disease progression. As a direct consequence, specific miRNA signatures may serve as potential biomarkers for the early detection and monitoring of AD and PD progression. This review aims to elucidate the complex interrelationships between the gut microbiota, trimethylamine-N-oxide (TMAO), microRNAs (miRNAs), and the central nervous system, and the implications of these connections in neurodegenerative diseases. In this context, an overview of the current neuroradiology techniques available for studying neuroinflammation and of the animal models used to investigate these intricate pathologies will also be provided. In summary, a bulk of evidence supports the concept that modulating the gut–brain communication pathway through dietary changes, the manipulation of the microbiome, and/or miRNA-based therapies may offer novel approaches for implementing the treatment of debilitating neurological disorders.