The primary goal for AD therapeutics is to prevent neuronal damage and improve cognitive function, a goal that is being pursued via many different approaches. Scott Noggle (The New York Stem Cell Foundation, New York, NY, USA) discussed stem cell technology as a way to specify cell types involved in neurodegeneration. In particular, induced pluripotent stem cell lines derived from AD patients could be especially valuable for both basic research and drug discovery screening programs; several familial AD lines are currently in development.
Various compounds that can improve cognition were presented in the rest of this session. Roberta Brinton (University of Southern California, Los Angeles, CA, USA) introduced allopregnanolone, a progesterone metabolite that is able to improve memory and neurogenic defects in 3xTg mice as well as in normally aged wild-type mice. These beneficial effects are only observed in transgenic mice younger than 1 year old, however, with the biggest improvements in young pre-plaque 3-month-old mice, indicating that allopregnanolone should be used as an early preventative treatment. Ottavio Arancio (Columbia University, New York, NY, USA) discussed cAMP responsive element-binding protein, which is a key transcription factor involved in synaptic plasticity that has been shown to be impaired by Aβ. Dr Arancio's laboratory recently demonstrated that sildenafil, an approved phosphodiesterase-5 inhibitor, improves cAMP responsive element-binding protein phosphorylation, synaptic plasticity, and learning and memory in APP/PS1 transgenic mice. After demonstrating that phosphodiesterase-5 is highly expressed in the human brain, Dr Arancio is working on optimizing lead phosphodiesterase-5 inhibitors.
Klotho, a secreted hormone that acts on multiple path-ways in aging and metabolism, was presented as another possible drug target by Carmela Abraham (Boston University School of Medicine, Boston, MA, USA). Dr Abraham discovered that while Klotho knockout mice have an accelerated aging phenotype that includes cognitive impairment, Klotho-overexpressing mice have increased life spans and enhanced resistance to oxidative stress. A high-throughput screen of chemical libraries identified several lead compounds that increase Klotho expression and will be tested for protective effects against Aβ-induced pathology.
High brain levels of striatal enriched tyrosine phosphatase (STEP) are found in several neurological diseases including AD. Paul Lombroso (Yale University, New Haven, CT, USA) found that increased STEP levels can impair synaptic plasticity and memory due to the dephosphorylation and subsequent internalization of glutamate receptors. A high-throughput screen identified STEP inhibitor lead compounds, which rescued behavioral tasks in transgenic mouse models a few hours after treatment, compared with the weeks of treatment necessary with memantine.
Another mechanism for cognitive dysfunction in AD could be hippocampal hyperexcitability, which is found in mild cognitive impairment patients and suggests that an attenuation of neuronal excitability could be a therapeutic strategy. As detailed by Michela Gallagher (Johns Hopkins University, Baltimore, MD, USA), the α5 subunit of the GABA-A receptor is highly expressed in the hippocampus, and agonists for this subunit, such as levetriacetam, can improve cognition in age-impaired rats; this drug is now being tested in elderly humans for cognition-improving effects.
Instead of targeting a specific pathway disrupted by pathological Aβ signaling, Susan Catalano (Cognition Therapeutics, Inc., Pittsburgh, PA, USA) presented efforts to block Aβ oligomer binding to neurons. Using a membrane tracking assay, Dr Catalano found several small-molecule compounds that competitively inhibit Aβ oligomer-induced perturbations and can rescue synaptic defects and cognitive impairments in transgenic AD mice. Current studies are underway to test for efficacy as a chronic, preventative treatment.