The Role of Chronic Inflammatory Bone and Joint Disorders in the Pathogenesis and Progression of Alzheimer's Disease

Abstract

Late-onset Alzheimer's Disease (LOAD) is a devastating neurodegenerative disorder that causes significant cognitive debilitation in tens of millions of patients worldwide. Throughout disease progression, abnormal secretase activity results in the aberrant cleavage and subsequent aggregation of neurotoxic Aβ plaques in the cerebral extracellular space and hyperphosphorylation and destabilization of structural tau proteins surrounding neuronal microtubules. Both pathologies ultimately incite the propagation of a disease-associated subset of microglia—the principle immune cells of the brain—characterized by preferentially pro-inflammatory cytokine secretion and inhibited AD substrate uptake capacity, which further contribute to neuronal degeneration. For decades, chronic neuroinflammation has been identified as one of the cardinal pathophysiological driving features of AD; however, despite a number of works postulating the underlying mechanisms of inflammation-mediated neurodegeneration, its pathogenesis and relation to the inception of cognitive impairment remain obscure. Moreover, the limited clinical success of treatments targeting specific pathological features in the central nervous system (CNS) illustrates the need to investigate alternative, more holistic approaches for ameliorating AD outcomes. Accumulating evidence suggests significant interplay between peripheral immune activity and blood-brain barrier permeability, microglial activation and proliferation, and AD-related cognitive decline. In this work, we review a narrow but significant subset of chronic peripheral inflammatory conditions, describe how these pathologies are associated with the preponderance of neuroinflammation, and posit that we may exploit peripheral immune processes to design interventional, preventative therapies for LOAD. We then provide a comprehensive overview of notable treatment paradigms that have demonstrated considerable merit toward treating these disorders.

The Occurrence of Alzheimer’s Disease and Parkinson’s Disease in Individuals With Osteoporosis: A Longitudinal Follow-Up Study Using a National Health Screening Database in Korea

“…Metals with neurotoxic properties have also been detected in the brain and cerebrospinal fluid from patients with neurodegenerative diseases, as they can cross the blood-brain barrier (Choi and Zheng, 2009 ). Inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, have been postulated to be involved in AD, PD, and osteoporosis (Zhang and Tian, 2014 ; Culibrk and Hahn, 2020 ). Third, oxidative stress and mitochondrial oxidative damage caused by aging may play a central role in these diseases because the risks of osteoporosis, AD, and PD increase significantly with age (Mattson et al, 1995 ; Yakunin et al, 2014 ; Domazetovic et al, 2017 ).…”

The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives

“…This is associated with HPA axis hyperactivity and glucocorticoid resistance, finally leading to uncontrolled inflammation [ 86 , 113 ]. Moreover, acute and chronic inflammation may aggravate existing neurodegenerative diseases [ 114 , 115 , 116 , 117 , 118 ]. Meta-analyses showed that levels of circulating pro-inflammatory cytokines (TNF, IL-1β and IL-6) are up-regulated in AD patients compared to age-matched control subjects and increased inflammation might even precede the outbreak of the disease [ 119 , 120 ].…”

Cerebral Organoids Derived from a Parkinson’s Patient Exhibit Unique Pathogenesis from Chikungunya Virus Infection When Compared to a Non-Parkinson’s Patient

“…While the gene expression data shows that the response to CHIKV involves changes in neurotransmission and immune response, clinical trials have shown that dysregulation of the inflammatory response can remodel neurotransmission, leading the changes in mood and cognition [ 13 , 65 , 66 ]. The reduced expression of ACHE has been linked to depression and cognitive deficits in human studies [ 67 , 68 , 69 ].…”