Prenatal Inflammation Effects on Blood-Brain Barrier Function and Alzheimer’s Disease-Related Pathologies Across the Lifespan

2022, 2023

It is well established that pathological blood-brain barrier (BBB) breakdown leads to neuronal injury and is associated with neurodegenerative disorders such as Alzheimer’s disease (AD) and related dementias. However, the physiological events leading to BBB breakdown associated with AD are not well understood. We recently demonstrated that fetal inflammation alters (BBB) development, leading to long-lasting disruption of BBB integrity and chronic brain inflammation persisting into adulthood. Our preliminary data suggest that these effects depend on the sustained activation of microglia, the brain’s resident immune cells. Ultimately, this leads to endogenous amyloid beta peptide clustering and cognitive and memory impairments in the aging offspring. These observations lead us to propose that incomplete BBB formation resulting from prenatal inflammation leads to a self-perpetuating cycle of chronic BBB leakage and brain inflammation lasting across the offspring’s lifespan, ultimately leading to accelerated brain senescence and the emergence of AD-like pathologies in aging. We will use pharmacological and genetic tools to uncover the molecular and cellular mechanisms of this self-perpetuating cycle of BBB disruption, microglial activation and brain inflammation promoting AD-like neuropathology. Our approaches explore vastly understudied mechanisms of the early etiology of vascular contributions to cognitive impairment and dementia, providing novel insights into the developmental origins and potential prevention of devastating diseases such as AD.

Funding to Date



Studies of Innate Immune Pathology


Alexandre Bonnin, Ph.D.