Preventing Alzheimer's Disease with Designer Lipids

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PROJECT SUMMARY Approximately 5.4 million people in the USA are afflicted with Alzheimer's Disease (AD), causing a marked cognitive decline and a doubling of the mortality rate for afflicted patients aged 70-80. AD (combined with simi- lar dementias) currently costs the USA healthcare system ~$277 billion a year. That cost is predicted to in- crease significantly as the population ages. Preventing and clearing amyloid beta (Aβ) plaque is key to long- term, effective treatment of AD. In 2013, administration of a chemically-derived bacterial product, monophos- phoryl lipid A (MPLA), a non-toxic derivative of the lipid A region of lipopolysaccharide (LPS), prevented the onset of AD-like symptoms in a mouse model, demonstrating a relatively inexpensive and effective route for AD prevention through weak Toll-like receptor 4 (TLR4) agonism. However, there are several problems with MPLA, the most important being the structural heterogeneity and inconsistency of the product. In contrast, we designed and expressed an MPLA-like functional homolog (lipooligosaccharide, LOS) in live bacterial strains that yield a more homogeneous product and are inexpensive to produce and purify. We have produced and tested a structurally-engineered MPLA-like LOS (Attenuated Lipid A Therapeutic, ALT), that is protec- tive from learning impairment in an AD-prone mouse model when given as a weekly low-dose injection. The underlying pathophysiology of AD likely starts very early (well before presentation as dementia) and it is still poorly understood, despite decades of effort. However, there are numerous reports suggesting that AD is the consequence of chronic inflammation in the brain, through persistent, strong stimulation of pattern recogni- tion receptors (PRR). Ligands for PRRs are numerous; specifically for TLR4 they include canonical LPS (also LOS and lipid A), but also several non-canonical molecules including Aβ peptide. Thus, competition at TLR4 may prevent inflammation associated with amyloid deposition by displacing more pro-inflammatory agonists. Further, microglial cells weakly activated through TLR4 were shown to have increased phagocytic activity in- cluding clearance of Aβ. We have demonstrated that ALT protects from AD-like learning impairment and this proposal will address protection in other early onset AD mouse models. Further, since ALT is produced from a live bacterial strain, we will investigate the use of the live strain as a potential probiotic therapy rather than a weekly injection of extracted LOS. This proposal aims to develop a live bacterial probiotic to prevent AD. This is an inexpensive and potentially highly impactful approach to AD prevention and therapy.