Herpes Simplex Virus Type 1 and Other Pathogens Are Key Causative Factors in Sporadic Alzheimer’S Disease
Total Page:16
File Type:pdf, Size:1020Kb
Journal of Alzheimer’s Disease 48 (2015) 319–353 319 DOI 10.3233/JAD-142853 IOS Press Review Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer’s Disease Steven A. Harrisa,∗ and Elizabeth A. Harrisb aSt. Vincent Medical Group, Northside Internal Medicine, Indianapolis, IN, USA bIndiana University School of Medicine, Indianapolis, IN, USA Handling Associate Editor: Roberta Mancuso Accepted 11 June 2015 Abstract. This review focuses on research in epidemiology, neuropathology, molecular biology, and genetics regarding the hypothesis that pathogens interact with susceptibility genes and are causative in sporadic Alzheimer’s disease (AD). Sporadic AD is a complex multifactorial neurodegenerative disease with evidence indicating coexisting multi-pathogen and inflamma- tory etiologies. There are significant associations between AD and various pathogens, including Herpes simplex virus type 1 (HSV-1), Cytomegalovirus, and other Herpesviridae, Chlamydophila pneumoniae, spirochetes, Helicobacter pylori, and various periodontal pathogens. These pathogens are able to evade destruction by the host immune system, leading to persistent infection. Bacterial and viral DNA and RNA and bacterial ligands increase the expression of pro-inflammatory molecules and activate the innate and adaptive immune systems. Evidence demonstrates that pathogens directly and indirectly induce AD pathology, including amyloid- (A) accumulation, phosphorylation of tau protein, neuronal injury, and apoptosis. Chronic brain infection with HSV-1, Chlamydophila pneumoniae, and spirochetes results in complex processes that interact to cause a vicious cycle of uncontrolled neuroinflammation and neurodegeneration. Infections such as Cytomegalovirus, Helicobacter pylori, and peri- odontal pathogens induce production of systemic pro-inflammatory cytokines that may cross the blood-brain barrier to promote neurodegeneration. Pathogen-induced inflammation and central nervous system accumulation of A damages the blood-brain barrier, which contributes to the pathophysiology of AD. Apolipoprotein E4 (ApoE4) enhances brain infiltration by pathogens including HSV-1 and Chlamydophila pneumoniae. ApoE4 is also associated with an increased pro-inflammatory response by the immune system. Potential antimicrobial treatments for AD are discussed, including the rationale for antiviral and antibiotic clinical trials. Keywords: Alzheimer’s disease, ApoE4, amyloid, Cytomegalovirus, dementia, Herpes simplex, neurodegeneration, pathogen THE ALZHEIMER’S DISEASE PATHOGEN the incidence is expected to rise. Current medical treat- HYPOTHESIS ment is not optimal, and thus an effective treatment is very much needed. The disease is associated with a Alzheimer’s disease (AD) is an inflammatory brain combination of environmental agents and genetic influ- disease that affects 20 million people worldwide and ences leading to inflammation of the brain, neuronal ∗ cell death, and progressive dementia [1]. Correspondence to: Steven A. Harris, MD, St. Vincent Medical AD is characterized by two main pathological fea- Group, Northside Internal Medicine, 2010W. 86th Street, Indianapo- lis, IN 46240, USA. Tel.: +1 317 415 6500; Fax: +1 317 415 6501; tures in the brain: senile plaques and neurofibrillary E-mail: [email protected]. tangles (NFTs). Senile plaques are extracellular and are ISSN 1387-2877/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License. 320 S.A. Harris and E.A. Harris / Pathogens are Key Causative Factors in Sporadic Alzheimer’s Disease predominantly made up of amyloid- (A), a peptide In 1982, Melvin Ball hypothesized that HSV-1 was cleavedfromthemuchlongeramyloid-proteinprecur- causative in AD. He proposed that latent HSV-1located sor(APP).Neurofibrillarytanglesareintracellularand in the trigeminal ganglia could reactivate and ascend comprised of abnormally phosphorylated tau protein. along known nerve pathways into the limbic system Tau protein is normally associated with microtubules in and areas of the brain most affected in AD [23]. neurons, and contributes to AD pathology in its phos- Herpes simplex encephalitis and AD affect the same phorylated state [2]. brain regions, including the frontal lobes, temporal The AD pathogen hypothesis states that pathogens lobes, and hippocampus. Herpes simplex encephali- actastriggers,interactingwithgeneticfactorstoinitiate tis survivors show cognitive, memory, and behavioral the accumulation and/or formation of A, hyperphos- decline. Other viruses implicated in neurological phorylated tau proteins, and inflammation in the AD disease include measles in subacute sclerosing panen- brain. Herpes simplex virus type 1 (HSV-1) and other cephalitis and human immunodeficiency virus in pathogens including Chlamydophila pneumoniae and HIV-associated dementia [22]. As with AD, both suba- Spirochetes are able to infect the brain, evade the host cute sclerosing panencephalitis [24] and HIV infection immune response, and are highly prevalent in the AD [25] are associated with the formation of phosphory- brain [3–9]. In vitro studies and animal models indi- lated tau protein and NFTs in the brain. cate that pathogens induce formation of A, amyloid plaques,andhyperphosphorylatedtauproteins[10–13]. Pathogens induce a glial inflammatory response and EPIDEMIOLOGICAL STUDIES: HSV-1 can directly and indirectly damage and destroy neurons HUMORAL RESPONSE, COGNITIVE [14–18]. Significant inflammatory cascades are acti- DECLINE, AND AD vated in the brains of AD patients [19, 20]. Together, these processes result in neurodegeneration and disease Epidemiological studies show an association progression. between viral infectious burden (IB) and cognitive This review examines evidence implicating HSV-1 decline. IB is defined as a composite serological mea- and Cytomegalovirus (CMV), both members of the sureofexposuretocommonpathogens[27].Strandberg Herpesviridae family, and the bacterial pathogens et al. measured seropositivity to HSV-1, HSV-2, CMV, Chlamydia pneumoniae, spirochetes, periodontal Chlamydiapneumoniae,andMycoplasmapneumoniae pathogens, and Helicobacter pylori as causative in in 383 elderly patients with cardiovascular disease. the pathogenesis of AD. Limited evidence is also Assessments including the Mini-Mental Status Exam- presented regarding the Herpesviridae Epstein Barr ination (MMSE) and the Clinical Dementia Rating Virus (EBV) and Human herpes virus 6 (HHV-6) were used to define cognitive impairment. Having three as possible contributing factors in AD pathogen- positive viral titers was associated with a 2.5 times esis. The multi-pathogen AD hypothesis does not higher risk for cognitive impairment after 12 months exclude toxins or other environmental co-factors [26]. Katan et al. [27] found an association between that may be involved in the pathogenesis of AD Herpesviridae and cognitive decline using a compos- and are reviewed elsewhere [21]. Pathogens were ite serologic measure of exposure to both bacterial selected based on the degree of significant cumulative (Chlamydia pneumoniae and Helicobacter pylori) evidence identified in an extensive PubMed literature and viral (CMV, HSV-1, and HSV-2) pathogens. As search. reviewed by Strandberg, the association was primarily driven by viral IB [28]. Letenneur et al. studied the risk of developing AD HERPES SIMPLEX VIRUS TYPE 1 according to the presence or absence of serum anti- HSV IgG and IgM antibodies by following 512 elderly HSV-1 is a neurotropic virus that infects most patientsinitiallyfreeofdementiafor14years.Thepres- humans, attaining 90% prevalence by the sixth decade ence of anti-HSV IgM antibodies is associated with of life. Infection is life long, as the virus resides in the primary infection or recent reactivation of HSV. In trigeminal ganglia of the peripheral nervous system in contrast, the presence of anti-HSV IgG antibodies indi- latent form with viral genome but no virions present. cates lifelong HSV infection [29]. Subjects who were Reactivation leads to viral replication and acute infec- IgM-positive at baseline showed a significantly higher tions known as herpes labialis, commonly referred to risk of developing AD (hazard ratio = 2.55). No signif- as cold sores [22]. icant increased risk for AD was found in IgG-positive S.A. Harris and E.A. Harris / Pathogens are Key Causative Factors in Sporadic Alzheimer’s Disease 321 subjects. Among the 43 IgM-positive subjects, only seen on morphometric magnetic resonance imaging 2 were IgG-negative, which supports recent HSV (MRI) of the brain compared to the HSV-1seronegative reactivation rather than primary infection in most of control group [34]. Poor cognitive test performance the IgM-positive subjects [29]. Similar results were correlated with decreased grey matter volume in some obtained in a longitudinal study by Lovheim¨ et al. of the same brain regions that distinguished the patient involving 3,432 elderly patients with a mean follow-up subgroups defined by HSV-1 status [34]. Several stud- time of 11.3 years. Baseline increased serum lev- ies have confirmed significant cognitive impairment in els of anti-HSV IgM antibodies were associated with HSV-1 IgG seropositive schizophrenia patients com- increased risk of developing AD by a factor of 2 [30]. pared to HSV-1IgG seronegative controls with average Thus, HSV reactivation, as indicated by the presence cohort ages