Neurodegenerative Protein Aggregating Disorders and a Tolerogenic Approach to Amelioration.
Inflammation is a common thread running through neurodegenerative diseases. The immune system mounts a highly inflammatory response to aggregated proteins that accumulate within neurological tissues. Normally the body gets rid of any aberrant, malformed, or mal-folded proteins through its intracellular and extracellular garbage disposal systems. The extracellular garbage disposal function is mainly accomplished throughout the body by the action of macrophages, and in the CNS, these macrophages are known as microglia. Among other functions, microglia are principally responsible for degradation and clearing of these proteins (assisted by astrocytes, a type of cell that augments and supports microglial function).
The various protein aggregation disorders are caused by various genetic and/or environmental factors, but all are characterized by a buildup of dysfunctional proteins. Protein manufacture is a vital function of all cells, including those in the CNS, but when problems occur that result in malformation or mis-folding, they must be removed so as not to interfere with normal neurologic function. In these diseases, however, these aberrant proteins accumulate and form bonds between themselves, resulting in aggregated clumps of proteinogenous garbage that is highly inflammatory. Inflammation overwhelms the garbage disposal system and renders it, essentially, dysfunctional.
The devastating neurological degeneration associated with diseases like Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis (ALS) progresses relentlessly over time as these aggregated proteins accumulate. The diseases differ in the type of protein that is produced and in the location within the CNS in which they are deposited; these characteristics determine the clinical symptomology and ultimately the determination of the particular disease.
The TregTherapeutics approach drives polarization and expansion of a Treg repertoire that has acquired specificity for the antigens derived from the aggregated proteins associated with a targeted neurodegenerative disease. These Tregs surveil the central nervous system (CNS), and upon recognition of CNS self-antigens, they inhibit inflammation that underlies neurodegeneration. The amelioration of neurodegenerative disease progression and symptoms is the expected outcome.
Tregs can play a critical role in the rejuvenation of microglial garbage disposal functionality by reducing inflammation. If inflammation is down-regulated via Treg cell signaling and the cytokines/chemokines they produce, then microglia can commence with normal garbage disposal activity that is critical to reduced symptomology and improved homeostasis.