The blood-brain barrier (BBB) is a tightly regulated barrier in the central nervous system. Though the BBB is thought to be intact during neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), recent evidence argues otherwise. Dysfunction of the BBB may be involved in disease progression, eliciting of peripheral immune response, and, most importantly, altered drug efficacy. In this review, we will give a brief overview of the BBB, its components, and their functions. We will critically evaluate the current literature in AD and PD BBB pathology resulting from insult, neuroinflammation, and neurodegeneration. Specifically, we will discuss alterations in tight junction, transport and endothelial cell surface proteins, and vascular density changes, all of which result in altered permeability. Finally, we will discuss the implications of BBB dysfunction in current and future therapeutics. Developing a better appreciation of BBB dysfunction in AD and PD may not only provide novel strategies in treatment, but will prove an interesting milestone in understanding neurodegenerative disease etiology and progression.

Recent studies suggest that the function of the blood brain barrier (BBB) is not static under normal physiological conditions and is likely altered in neurodegenerative disease. Prevailing thinking about CNS function, and neurodegenerative disease in particular, is neurocentric excluding the impact of factors outside of the CNS. This review challenges this perspective and discusses recent reports suggesting the involvement of peripheral factors including toxins and elements of adaptive immunity that may not only play a role in pathogenesis, but also progression of neurodegenerative diseases. Central to this view is neuroinflammation. Several studies indicate that the neuroinflammatory changes that accompany neurodegeneration affect the BBB or its function by altering transport systems, enhancing immune cell entry, or influencing the BBB’s role as a signaling interface. Such changes impair the BBB’s normal homeostatic function and affect neural activity. Moreover, recent studies reveal that alterations in BBB and its transporters affect the entry of drugs used to treat neurodegenerative diseases. Incorporating BBB compromise and dysfunction into our view of neurodegenerative disease leads to inclusion of peripheral mediators in its pathogenesis and progression. In addition, this changing view of the BBB raises interesting new therapeutic possibilities for drug delivery as well as treatment strategies designed to reinstate normal barrier function.

Despite decades of research and the development of a large group of animal models, our understanding of the mechanisms responsible for the progressive loss of dopamine neurons in Parkinson's disease (PD) is unknown. So-called neuroprotective studies demonstrate that a vast group of molecules readily attenuate the dopamine (DA) neuron loss produced by DA neurotoxin insult. Despite these successes, these neuroprotective strategies have been surprisingly ineffective in patients. This may reflect the fact that the initial pathogenic event and the subsequent disease progression is a consequence of different mechanisms. As we began to think about this disconnect, we discovered that animals exposed to DA neurotoxins exhibited blood-brain barrier (BBB) dysfunction. If the BBB in PD patients is disrupted, then the barrier that normally segregates peripheral vascular factors from brain parenchyma is no longer present. Immune cells could then enter brain and produce a self-perpetuating (progressive) degenerative process. In this review, we propose that peripheral immunity contributes to the degenerative process of PD and may be responsible for the progressive nature of the disease. This hypothesis is supported by a broad and diverse literature that is just beginning to come together to suggest that PD is, in part, an autoimmune disease. In order to understand this hypothesis, the reader must question the conventional wisdom that the BBB is intact in PD, the brain is an immune privileged area, and that pathogenic insult and disease progression may reflect different mechanisms.