Many recent and ongoing clinical trials for the treatment of Alzheimer’s disease are based on the goal of increasing β-amyloid clearance from the brain. A pivotal clinical trial with this approach studied active immunization of patients with AD against β-amyloid and the trial was stopped prematurely when some subjects developed a CNS angiitis. At autopsy, β-amyloid plaques had been successfully cleared from parenchyma, but vascular deposition of β-amyloid, cerebral amyloid angiopathy (CAA), was increased and in some cases dramatically so. This study clarified the importance of CAA as a significant factor in the neurobiology of AD. In previous work, we have studied the clinical course, neuroimaging, neuropathology and neurobiology of CAA in detail and based on this experience, we hypothesize that a successful intervention against AD will need to improve both parenchymal and vascular β-amyloid pathology. There is a critical need to identify a therapeutic target that will improve all of these major neuropathologies associated with Alzheimer’s disease. As a result, we have turned our focus to studying intracellular β-amyloid production and degradation in lysosomes in the hope that improving intracellular lysosomal function may prevent the formation of parenchymal β-amyloid deposits and intraneuronal protein aggregates without worsening CAA.
Through this work, we discovered that there is extensive accumulation of lysosomes within dystrophic axon segments around β-amyloid plaques forming a halo around the plaques.
This neuropathological structure is present around essentially every β-amyloid plaque and is present from the earliest detectable stages of β-amyloid pathology. We also discovered that these lysosomes are abnormal, not just because of they accumulate within distended and dystrophic axon segments, but also because they are severely deficient in luminal proteases. Key proteins to AD neurobiology also accumulate in these structures, including β-secretase, amyloid precursor protein and presinilin, among others, which suggests that this is likely the site within neurons where β-amyloid is produced. These features make this structure of particular interest as a therapeutic target, but the precise role it plays in the neurobiology of AD and cognitive loss remains to be clearly defined. It is not clear why these lysosomes are in neuritic axons, why they are deficient in proteases or whether this is protective or harmful. We are working with an animal model which reproduces this pathological structure will enable us to test the role of this structure in AD and CAA.