Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer's Disease?

Abstract

Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of pTau. These findings led to the "beta-amyloid hypothesis" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease. Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection - Aβ - AD and discuss future possible treatments based on this paradigm.

Keywords: Alzheimer’s disease; amyloid beta; biofilms; blood–brain barrier; infections; monocytes/macrophages; peripheral innate immune system; senile plaques.

FIGURE 1

Pathogenesis of Alzheimer’s disease (AD) according to an infection hypothesis incorporating the old amyloid beta hypothesis. Peripheral microbiomes are the source of microorganisms. In the periphery, they activate the innate immune system and cause inflammation which favors penetration of microorganisms either via the blood-stream or transported by monocytes/macrophages through the blood–brain barrier (BBB) into the brain. In the brain they form biofilms which integrate Aβ (pathogen-induced) to form senile plaques. Disruption of the BBB comes both from outside the brain via peripheral inflammatory mediators as well as from within the brain by the cytokines and inflammatory cells having already penetrated the BBB as well as mediators generated by microglia that have been stimulated by chronic infections. Genetics/epigenetics, stress, and aging affect both sides. Together they form a vicious circle, originating (and perpetuated) by chronic infections or pathogen reactivation. An additional smaller amplifying circle exists between plaques and biofilms which stimulate neuroinflammation in the brain. This process leads to neuron death and eventually to AD.