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.
Highlights
Canonical central nervous system (CNS) Targets for AD TherapyPathological β-amyloid accumulations were among the earliest recorded physiological manifestations of AD (Tomlinson et al, 1970) and, along with neurofibrillary tangles, are considered a hallmark of AD-related neurodegeneration
In AD, through a series of complex immunological and neurophysiological events that transpire well before the onset of cognitive impairment (Braak et al, 2006), tau proteins undergo a series of post-translational modifications—including and hyperphosphorylation
The net effect of aging on autophagy on the microscopic scale requires further investigation: while age-related senescence contributes to a global reduction in autophagy (Caramés et al, 2010), the resulting accumulation of oxidative stress may induce autophagy predominantly in inflammatory mediators involved in disease pathology
Summary
Canonical CNS Targets for AD TherapyPathological β-amyloid accumulations were among the earliest recorded physiological manifestations of AD (Tomlinson et al, 1970) and, along with neurofibrillary tangles, are considered a hallmark of AD-related neurodegeneration. Longitudinal clinical studies further implicate early chronic peripheral inflammation in the preponderance of neurodegenerative disease: individuals with higher levels of pro-inflammatory cytokines in midlife are at a significantly higher risk for cognitive decline as they age (Walker et al, 2019b)—those who maintained aberrant levels for multiple decades were found to be especially prone to debilitating neurodegeneration via reduced brain volume and abnormal white matter microstructural integrity (Walker et al, 2017, 2018).
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