Title

Selective enhancement of lysosomal responses clears Alzheimer's disease protein deposits and concomitantly reduces synaptic and behavioral deficits

Date of Completion

January 2008

Keywords

Health Sciences, Pharmacology

Degree

Ph.D.

Abstract

Protein deposition is a characteristic of Alzheimer's disease (AD) in which pathogenic accumulations of paired helical filaments (PHFs) and amyloid-β peptides (e.g., Aβ1-42) are thought to cause synaptic and cognitive decline, leading to the behavioral deficits seen in many neurodegenerative disorders with dementia. Protein accumulation stress triggers compensatory protein clearance responses in AD and model systems, and understanding such lysosomal responses and their modulation has led to a potential therapeutic strategy. The key basis of the strategy is that lysosomes are the primary digestive site for exhausted and/or misfolded proteins. This thesis tested the hypothesis that enhancing degradative responses through pharmacologically-controlled modulation of the lysosomal system leads to protein clearance and reduced AD pathogenesis. Using the hippocampal slice model, distinct types of protein clearance systems were found to be activated in response to the induction of PHF deposits or uptake of Aβ1-42, perhaps to offset the transport failure, synaptic decline, and axonopathy evident in the model. When the enzyme expression of lysosomal responses was enhanced with a small-molecule lysosomal modulator, Z-Phe-Ala-diazomethylketone (PADK), the deficits exhibited in the slice model were reduced. In vivo lysosomal modulation was also elicited in rat and mouse brains after systemic PADK injections, resulting in dose-dependent increases in different cathepsin enzymes. Cathepsins are one of several classes of protein-degrading lysosomal hydrolases. The lysosomal modulation was found to be induced in the absence of adverse effects to neuronal markers, behavior, or major organ systems. To test whether the lysosomal modulator increases clearance of AD-type protein accumulation and promotes neuronal and functional integrity, PADK was administered to transgenic mouse models expressing human genes linked to AD. Different measures of Aβ were reduced by PADK treatment, corresponding with the marked increases of cathepsins B and D. The synaptic and behavior deficits evident in the mouse models were both reduced by the lysosomal modulator, in most cases to levels found in non-transgenic control mice. The synaptic-behavior linkage fits well with the wide belief that synaptic deterioration is the best correlate of the cognitive decline seen in dementias. Interestingly, the extent of PADK-mediated clearance, synaptic protection, and memory improvement was similar at mild and more severe levels of AD pathology in the mouse models. The results show that enhancing the lysosomal system promotes clearance of hallmark AD accumulation events and reduces related pathogenesis. They also suggest that a compensatory lysosomal response is one of what is likely many determining factors for AD progression. Controlled modulation of the lysosomal system may be valuable for treating a variety of accumulation disorders including AD, frontotemporal dementia, and Parkinson's, as well as certain lysosomal storage diseases. ^