Fungal infection in patients with Alzheimer’s disease.
J Alzheimers Dis. 2014;41(1):301-11. doi: 10.3233/JAD-132681.
Alonso R1, Pisa D1, Marina AI1, Morato E1, Rábano A2, Carrasco L1.
1Centro de Biología Molecular Severo Ochoa CSIC-UAM, C/ Nicolás Cabrera, 1 Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
2 Department of Neuropathology and Tissue Bank, Unidad de Investigación Proyecto Alzheimer, Fundación CIEN, Instituto de Salud Carlos III, Madrid, Spain.
Alzheimer’s disease is a progressive neurodegenerative disorder that leads to dementia mainly among the elderly. This disease is characterized by the presence in the brain of amyloid plaques and neurofibrillary tangles that provoke neuronal cell death, vascular dysfunction, and inflammatory processes. In the present work, we have analyzed the existence of fungal infection in Alzheimer’s disease patients. A proteomic analysis provides compelling evidence for the existence of fungal proteins in brain samples from Alzheimer’s disease patients. Furthermore, PCR analysis reveals a variety of fungal species in these samples, dependent on the patient and the tissue tested. DNA sequencing demonstrated that several fungal species can be found in brain samples. Together, these results show that fungal macromolecules can be detected in brain from Alzheimer’s disease patients. To our knowledge these findings represent the first evidence that fungal infection is detectable in brain samples from Alzheimer’s disease patients. The possibility that this may represent a risk factor or may contribute to the etiological cause of Alzheimer’s disease is discussed.
KEYWORDS: Alzheimer’s disease; brain proteomics; fungal DNA; fungal PCR; fungal infection
The study of neurodegenerative diseases is very important in present day medicine. Unfortunately, in most cases the etiology of these illnesses remains unknown. Thus, the cause of multiple sclerosis, amyotrophic lateral sclerosis, Parkinson´s disease or Alzheimer’s disease (AD) is still unidentified. It is vital to understand the etiology of these diseases in order to implement the necessary treatment to curb the loss of neurons. Currently, there is no curative therapy for AD and only some symptoms are ameliorated. There is at present over 30 million AD patients worldwide and this number will increase to about 65 million by 2030. Several theories have been put forward as the potential cause of AD. The actual dogma is known as the “amyloid cascade hypothesis”. According to this theory, the initial symptoms of the disease can be explained by the deposition of amyloid peptide that is produced by an imbalance between the production and clearance of this peptide. However, this hypothesis fails to explain several clinical symptoms of the disease, such as the pathology of blood vessels and inflammation. Furthermore, strategies aimed to reduce β-amyloid burden have failed to improve symptoms in clinical trials. Suggestions that AD is caused by herpesvirus or bacterial infections have also been made. However, to date there is no experimental support for these theories. We have advanced the idea that AD is caused by fungal infections. To our knowledge, this is the first time that fungal infections have been proposed in the etiology of AD. In support of this idea, compelling evidence has been provided by our group to demonstrate that AD patients contain fungal polysaccharides, proteins and DNA in peripheral blood (1). In addition, we have demonstrated the presence of fungal proteins and DNA in brain samples from AD patients. Moreover, in brain sections from deceased patients, fungi are observed by the use of specific anti-fungal antibodies (2). Figure 1 shows that these fungi are not found in brain sections (frontal cortex) from a control subject, whereas fungal material and spherules are clearly detected in AD patient. Our observations also indicate that several fungal species are present in AD brain samples. Thus, Saccharomyces cerevisiae, Malassezia spp, Penicillium spp or Phoma have been characterized in these samples. The concept that arises from these studies is that mixed fungal infections can be present in a single patient and the actual fungal species may vary from patient to patient. These observations can account for the variation in the evolution and severity of symptoms observed in individual AD patients. The premise that the etiology of AD is of fungal origin is consistent with all the experimental evidence known to date. Thus, this infection can trigger the appearance of amyloid deposits observed in the central nervous system since amyloid peptide has potent antifungal activity. Most probably, this infection induces neurons to increase the synthesis and export of the amyloid precursor giving rise to depositions of the antifungal peptide. Another important aspect of AD is the inflammation and vascular dystrophy observed in many AD patients. Once again, this is consistent with the fact that fungal infections can induce inflammatory reactions as well as vascular modifications. Inflammatory cytokines are elevated not only in the central nervous system but also in peripheral blood, probably as a consequence of disseminated fungal infection. Additionally, it is known that in 1-2% of patients AD is due to their genetic background. Genetic predisposition in this small percentage of AD patients is in good agreement with the possible fungal origin of this disease since the genetic background of a given person may determine susceptibility to fungal colonization. Another important aspect is that in the few cases reported in the scientific literature on AD patients that have been treated with antifungal agents, the symptoms of the disease were markedly reversed. These patients were treated with antifungals because of a suspicion of fungal infection unrelated to AD. In conclusion, all the clinical symptoms known for AD can be explained if we consider that this is a disseminated fungal disease. To determine whether or not mycoses are the cause of AD, clinical trials with antifungal compounds should be carried out. These clinical trials would determine whether the etiology of AD is of fungal origin and, if this is the case, AD patients may benefit from the use of available antifungal agents.
1. Alonso R, Pisa D, Rábano A, Carrasco L. Alzheimer’s disease and disseminated mycoses. Eur J Clin Microbiol Infect Dis. 2014 Jul;33(7):1125-32.
2. Pisa D, Alonso R, Juarranz A, Rábano A, Carrasco L. Direct visualization of fungal infection in brains from patients with Alzheimer’s disease. J Alzheimers Dis. 2015 Jan 1;43(2):613-24.
Fig1. Immunohistochemistry analysis of brain sections (frontal cortex) of a control subject (left) and AD patient (right). The nucleus of the neurons appears in blue, whereas the fungal material is observed in green. Neurofilaments are shown in red