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. 2015 Oct 15:5:15015.
doi: 10.1038/srep15015.

Different Brain Regions are Infected with Fungi in Alzheimer's Disease

Diana Pisa  1 , Ruth Alonso  1 , Alberto Rábano  2 , Izaskun Rodal  2 , Luis Carrasco  1
Affiliations

Different Brain Regions are Infected with Fungi in Alzheimer's Disease

Diana Pisa et al. Sci Rep. .

Abstract

The possibility that Alzheimer's disease (AD) has a microbial aetiology has been proposed by several researchers. Here, we provide evidence that tissue from the central nervous system (CNS) of AD patients contain fungal cells and hyphae. Fungal material can be detected both intra- and extracellularly using specific antibodies against several fungi. Different brain regions including external frontal cortex, cerebellar hemisphere, entorhinal cortex/hippocampus and choroid plexus contain fungal material, which is absent in brain tissue from control individuals. Analysis of brain sections from ten additional AD patients reveals that all are infected with fungi. Fungal infection is also observed in blood vessels, which may explain the vascular pathology frequently detected in AD patients. Sequencing of fungal DNA extracted from frozen CNS samples identifies several fungal species. Collectively, our findings provide compelling evidence for the existence of fungal infection in the CNS from AD patients, but not in control individuals.

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Figures

Figure 1
Figure 1. Immunohistochemistry analysis of tissue sections from different regions of the CNS using anti-C. glabrata antibodies.
CNS sections from patient AD1 and control individual C1 were obtained from fixed tissue and immunohistochemistry analysis by confocal microscopy was carried out as detailed in Materials and Methods. EFC: external frontal cortex; CEH: cerebellar hippocampus; ERH: entorhinal cortex/hippocampus; CP: choroid plexus. DAPI appears in blue, anti-C. glabrata is shown in green and TauT100 in red. The different panels in the figure are indicated. Scale bar: 5 μm.
Figure 2
Figure 2. Immunohistochemistry analysis of CNS sections from patient AD1 using different anti-fungal antibodies.
Immunohistochemistry analysis of different CNS sections from patient AD1 was carried out as indicated in Fig. 1. EFC: external frontal cortex; CEH: cerebellar hippocampus; ERH: entorhinal cortex/hippocampus. DAPI appears in blue, anti-C. famata, anti-C. albicans, anti-P. betae and anti-S. racemosum are shown in green and human neurofilament in red. The different panels in the figure are indicated. Scale bar: 10 μm.
Figure 3
Figure 3. DAPI staining of nuclei of the different fungal morphologies.
DAPI staining is shown in magenta to visualize more clearly the fungal nuclei. Immunoreactivity with the fungal antibodies indicated is shown in green. Panels A–G and S: anti-C. glabrata as primary antibody. Panels H–J, T, U, W: anti-C. famata as primary antibody. Panels: K–M, V, X: anti-C. albicans as primary antibody. Panels N, O, Y, Z: anti-S. racemosum. as primary antibody. Panels P-R: anti- P. betae as primary antibody. Panels K, L, S, T, U, Y: EFC of patient AD1. Panels A, H, M–Q, X: CEH of patient AD1. Panels I, J, R, V, W, Z: ERH of patient AD1. Panels B, C, D: CP of patient AD1. Panel E: ERH of patient AD3. Panel F: ERH of patient AD4. Panel G: ERH of patient AD9. Scale bar: 5 μm is the same for all panels shown in the figure.
Figure 4
Figure 4. Immunohistochemistry analysis of entorhinal cortex sections from ten different AD patients.
Entorhinal cortex sections from ten different AD patients were incubated with different antibodies (anti-C. glabrata, anti-C albicans and anti-P. betae) and are shown in green; human α-tubulin immunostaining is shown in red. Double immunofluorescence assay and confocal microscopy was carried out as indicated in Fig. 1 and Materials and Methods. DAPI appears in blue. Scale bar: 5 μm.
Figure 5
Figure 5. Fungal bodies in CNS blood vessels from patient AD1 detected by immunohistochemistry.
Double immunofluorescence assay analyzed by confocal microscopy as described in Materials and Methods. Blood vessels from different CNS regions from patient AD1 are shown. Panels A–E: EFC. Panels F and G: ERH. Panels H–L: CP. Panels A and I: anti-C. famata as primary antibody. Panels B, C, J: anti-C. albicans as primary antibody. Panels D, G, K: anti-P. betae as primary antibody. Panels E and L: anti-S. racemosum as primary antibody. Panels F and H: anti-C. glabrata as primary antibody. Anti-fungal antibodies are shown in green. An anti-human neurofilament antibody was used in all panels, except panels F and H, which were stained with anti-TauT100 antibodies (red.) DAPI appears in blue. Scale bar: 10 μm.
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