Recent findings have improved our understanding of the multifactorial nature of AD. While in early asymptomatic stages of AD, increased amyloid-β synthesis and tau hyperphosphorylation play a key role, while in the latter stages of the disease, numerous dysfunctions of homeostatic mechanisms in neurons, glial cells, and cerebrovascular endothelium determine the rate of progression of clinical symptoms. The main driving forces of advanced neurodegeneration include increased inflammatory reactions in neurons and glial cells, oxidative stress, deficiencies in neurotrophic growth and regenerative capacity of neurons, brain insulin resistance with disturbed metabolism in neurons, or reduction of the activity of the Wnt-β catenin pathway, which should integrate the homeostatic mechanisms of brain tissue. In order to more effectively inhibit the progress of neurodegeneration, combination therapies consisting of drugs that rectify several above-mentioned dysfunctions should be used. It should be noted that many widely-used drugs from various pharmacological groups, "in addition" to the main therapeutic indications, have a beneficial effect on neurodegeneration and may be introduced into clinical practice in combination therapy of AD. There is hope that complex treatment will effectively inhibit the progression of AD and turn it into a slowly progressing chronic disease. Moreover, as the mechanisms of bidirectional communication between the brain and microbiota are better understood, it is expected that these pathways will be harnessed to provide novel methods to enhance health and treat AD.
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http://dx.doi.org/10.2174/1570159X19666211202124239 | DOI Listing |
Nat Rev Mol Cell Biol
January 2025
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
Maintaining homeostasis is essential for continued health, and the progressive decay of homeostatic processes is a hallmark of ageing. Daily environmental rhythms threaten homeostasis, and circadian clocks have evolved to execute physiological processes in a manner that anticipates, and thus mitigates, their effects on the organism. Clocks are active in almost all cell types; their rhythmicity and functional output are determined by a combination of tissue-intrinsic and systemic inputs.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
University of California, San Diego, San Diego, CA, USA.
Background: Microglia are the major innate immune cells of the brain and play diverse roles in brain development and homeostasis. In the context of Alzheimer's disease, microglia acquire new phenotypes that can exert protective or pathogenic roles. Single cell and single nuclei RNA sequencing experiments have defined molecular signatures of different disease-associated microglia states associated with protective or pathogenic functions, but the mechanisms driving these transitions are not known.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
USC School of Pharmacy, Los Angeles, CA, USA.
Background: Cellular senescence is a hallmark of aging and has been implicated in several neurodegenerative diseases including Alzheimer's disease (AD). Senescence cells undergo changes in gene expression and metabolism and can exhibit a so-called "senescence-associated secretory phenotype" (SASP) characterized by increased secretion of pro-inflammatory molecules and factors which can damage nearby cells, contributing to AD pathology progression.
Method: In this study, we determined mechanisms of cellular senescence using human postmortem brain samples, cellular models, and APOE4 animal models.
Alzheimers Dement
December 2024
Brain and Mind Research Institute, new york, NY, USA.
Background: DAP12 (DNAX-activation protein 12 or TYROBP) functions as a pivotal adaptor, facilitating signal transmission from surface immune receptors on microglia, including TREM2-a known risk gene for Alzheimer's disease (AD). Previous studies showed that DAP12-deficient mice exhibit resistance to tau toxicity in a tauopathy model, manifesting reduced brain inflammation and improved cognition, despite increased tau pathology. However, the precise mechanism underlying how DAP12 deficiency enhances resilience to tauopathy remains elusive.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
University of Bristol, Bristol, United Kingdom.
Background: Homeostatic sleep regulation is theorized to be governed by the 'Two Process Model' where circadian rhythm (process C) and homeostatic sleep pressure (process S) interact to determine sleep versus wakefulness. Sleep pressure accumulated during prolonged wakefulness increases the duration and intensity of subsequent 'recovery' sleep. Multiple sleep abnormalities are associated with Alzheimer's Disease (AD) Dementia and Lewy Body Dementia (LBD).
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