Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits

Abstract

Bloodborne infections with Candida albicans are an increasingly recognized complication of modern medicine. Here, we present a mouse model of low-grade candidemia to determine the effect of disseminated infection on cerebral function and relevant immune determinants. We show that intravenous injection of 25,000 C. albicans cells causes a highly localized cerebritis marked by the accumulation of activated microglial and astroglial cells around yeast aggregates, forming fungal-induced glial granulomas. Amyloid precursor protein accumulates within the periphery of these granulomas, while cleaved amyloid beta (Aβ) peptides accumulate around the yeast cells. CNS-localized C. albicans further activate the transcription factor NF-κB and induce production of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor (TNF), and Aβ peptides enhance both phagocytic and antifungal activity from BV-2 cells. Mice infected with C. albicans display mild memory impairment that resolves with fungal clearance. Our results warrant additional studies to understand the effect of chronic cerebritis on cognitive and immune function.

Foreign body responses in central nervous system mimic natural wound responses and alter biomaterial functions

“…Lastly, our findings inform the understanding of CNS wound responses by demonstrating and characterizing how FBRs fall firmly within the framework of the conserved multicellular biology of such responses. In this regard, we also add to the growing evidence [48][49][50][51][52][53] that APP accumulation and the acute formation of Aβ are consequent responses to neural tissue injury that occur in direct proportion to the level of neuronal and axonal damage, and are thus part of the conserved biology of CNS wound responses and FBRs.…”

“…The formation of beta-amyloid (Aβ) via cleavage of APP by β-and γ-secretase enzymes is increasingly recognized as a normal occurrence during CNS wound responses [52,53]. We evaluated the progression of APP to Aβ ( Fig.…”

“…These observations are consistent with growing evidence that APP accumulation and subsequent Aβ formation are part of a conserved innate wound and foreign body response. While the specific functions of Aβ production in this context are not yet defined, recent evidence suggests that Aβ may exert antimicrobial activities [52,53].…”

New Insights Into the Pathogenesis of Alzheimer's Disease

“…HHV-6A, in particular, is involved in the host regulation of many AD risk genes such as BACE1 and APBB2 and promotes Aβ precipitation and neuronal loss by inhibiting miR-155 (114). Candida albicans, the pathogen of oral ulcers, was reported to result in a gelatinous granuloma (FIGG), similar to AD plaques and primary symptoms of suspected AD, such as memory loss (115).…”

Rationale for the development of an Alzheimer’s disease vaccine

“…[87][88][89][90] Brain infection by viruses, fungi, or bacteria induces secretion of Aβ, which sticks to the microbe or virus and forms aggregates around it, encasing it. 86,88,[90][91][92][93][94] Viral DNA or bacteria have been found inside amyloid plaques. 86,88,91,93,95 Aβ activates an immune response, including stimulation of microglia, inflammation, release of cytokines, complement activation, and further secretion of Aβ itself, which may explain the localized accumulation of Aβ in amyloid plaques and the chronic nature of AD.…”