The Role of Inflammation and Infection in Age-Related Neurodegenerative Diseases: Lessons From Bacterial Meningitis Applied to Alzheimer Disease and Age-Related Macular Degeneration

Abstract

Age-related neurodegenerative diseases, such as Alzheimer disease (AD) and age-related macular degeneration (AMD), are multifactorial and have diverse genetic and environmental risk factors. Despite the complex nature of the diseases, there is long-standing, and growing, evidence linking microbial infection to the development of AD dementia, which we summarize in this article. Also, we highlight emerging research findings that support a role for parainfection in the pathophysiology of AMD, a disease of the neurosensory retina that has been shown to share risk factors and pathological features with AD. Acute neurological infections, such as Bacterial Meningitis (BM), trigger inflammatory events that permanently change how the brain functions, leading to lasting cognitive impairment. Neuroinflammation likewise is a known pathological event that occurs in the early stages of chronic age-related neurodegenerative diseases AD and AMD and might be triggered as a parainfectious event. To date, at least 16 microbial pathogens have been linked to the development of AD; on the other hand, investigation of a microbe-AMD relationship is in its infancy. This mini-review article provides a synthesis of existing evidence indicating a contribution of parainfection in the aetiology of AD and of emerging findings that support a similar process in AMD. Subsequently, it describes the major immunopathological mechanisms that are common to BM and AD/AMD. Together, this evidence leads to our proposal that both AD and AMD may have an infectious aetiology that operates through a dysregulated inflammatory response, leading to deleterious outcomes. Last, it draws fresh insights from the existing literature about potential therapeutic options for BM that might alleviate neurological disruption associated with infections, and which could, by extension, be explored in the context of AD and AMD.

Neuronal Damage and Neuroinflammation, a Bridge Between Bacterial Meningitis and Neurodegenerative Diseases

“…In patients with AD both the onset and the progression of the disease has been associated with a history of infection in the patient’s life; in particular, the incidence of pneumonia, as well as respiratory and urinary tracts infections, has been shown to be higher in AD patients, traditionally considered a consequence of the disease, but can also be related to its onset (Kountouras et al, 2006 ; Natalwala et al, 2008 ; Miklossy, 2011 ; Too et al, 2021 ). Delirium, on the other hand, often caused by CNS infection, is correlated with an acceleration in the progression towards dementia (McManus and Heneka, 2017 ).…”

Progressive cognitive impairment after recovery from neuroinvasive and non-neuroinvasive Listeria monocytogenes infection

“…In contrast, the other may/may not combine these peripheral signals with the effects of CD8 + T-lymphocytes recruited into the brain during the acute infection and which are retained after bacteria have been eliminated. The ability to identify and measure these differences experimentally is a key step towards understanding the means by which different infections exert neuro-toxic actions and will give insight towards developing effective therapies for ameliorating cognitive decline after infection and other related conditions ( 77 , 78 ).…”

Bisphenol F Impaired Zebrafish Cognitive Ability through Inducing Neural Cell Heterogeneous Responses

“…In this study, significant increases in the levels of inflammatory cytokines (TNFα, IL-6, and IL-1β) were observed in BPF-treated brains, which further confirmed the occurrence of neural inflammation. Neuroinflammation has been generally recognized as a factor negatively regulating neurogenesis and regeneration, and mammalian assays have suggested that the release and accumulation of inflammatory factors in the neural system parallel the cognitive dysfunction induced by neurodegenerative diseases, bacterial infection, and surgery. − Therefore, we considered the abnormal cognitive behaviors of BPF-treated zebrafish associated with the activation of immune cells and neuroinflammation. A previous study also indicated that embryonic BPF exposure results in neural inflammation by activating microglia and then results in the abnormal behavioral response of zebrafish larvae .…”