Applications of Nanotechnology in Alzheimer’s Disease BioE 494 – Atomic and Molecular Nanotechnology Fall 2007 Deivya Bansal

Outline What is Alzheimer’s disease? What is some of the current research being done? How does nanotechnology play a role? What are some future directions that can be taken using nanotechnology?

WHAT IS ALZHEIMER'S DISEASE?

Alzheimer’s Disease Neurodegenerative disease Most common form of dementia ~60% worldwide Memory, cognition, thought and language are primary impact areas Costs over $100 billion a year Final confirmation occurs via post-mortem inspection Presence of plaques and tangles

Alzheimer’s Disease Plaques Incorrectly folded amyloid-β proteins Recall the 4 structures of protein folding Neurofibrillary tangles Hyperphosphorylation of tau protein Makes it aggregate Found within neurons of those with AD Not completely understood

Alzheimer’s Disease This shows images of normal brain tissue versus brain tissue afflicted with Alzheimer’s disease. 1 This image shows positron emission tomography (PET) of a normal brain versus one with Alzheimer’s disease. 1 1 Mattson, Mark. “Pathways Towards and Away from Alzheimer’s Disease.” Nature 430 (2004):

Diagnosis of Alzheimer’s disease 3 Sunderland, Trey; Hampel, Harald; Takeda, Masatoshi; et.al. “Biomarkers in the Diagnosis of Alzheimer’s Disease: Are We Ready?” Journal of Geriatric Psychiatry and Neurology 13 (2006):

WHAT IS SOME OF THE CURRENT RESEARCH BEING DONE?

Current Research Understand etiology of disease Includes specimen examination EEG examination Detecting and testing biomarkers in cerebrospinal fluid and in plasma Show biochemical impact on neurons Development of new drugs aimed to keeping biochemical balance within brain

Current Research Lumbar puncture being performed Access to cerebrospinal fluid ~150 mL of fluid is in direct contact with brain See biochemical makeup of fluid 2 Andreasan, Niel and Blennow,Kaj. “CSF biomarkers for mild cognitive impairment and early Alzheimer’s disease.” Clinical Neurology and Neurosurgery 107 (2005):

HOW DOES NANOTECHNOLOGY PLAY A ROLE?

Use of Nanotechnology Detection of biomarkers Drug Delivery

Nanotechnology and Biomarker Detection

Bio-Barcode Assay Ultrasensitive Can detect any concentration making it ideal for AD diagnosis Uses oligonucleotide-modified nanoparticles Localized Surface Plasmon Resonance (LSPR) Nanosensor Sensitive to changes in refractive index near surfaces of gold and silver nanoparticles

Bio-Barcode Assay 3 Keating, Christine D. “Nanoscience enables ultrasensitive detection of Alzheimer’s biomarker.” Proceedings of the National Academy of Sciences 102 (2005): Georganopoulou, Dimitra G., et al. “Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer’s disease.” Proceedings of the National Academy of Sciences 102 (2005):

Nanotechnology and Drug Delivery Nanoparticle encapsulated Thioflavin-T Antioxidant Chelation Therapy Iron Chelate 4 Liu, Gang et al. “Nanoparticle Iron Chelators: A new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance.” Neuroscience Letters 406 (2006): Hartig, Wolfgang, et.al. “Electron microscopic analysis of nanoparticles delivering thioflavin- T after intrahippocampal injection in mouse: implications for targeting β-amyloid in Alzheimer’s disease.” Neuroscience Letters 338 (2003):

Nanoparticle Encapsulation Targeted drug delivery Testing done for: Vitamin E Thioflavin-T Nanoparticles similar to LDL Identifies with LDL receptors Easier passage through blood brain barrier

Chelation Therapy Chelator – Compound that binds to free metal ions Iron chelator most commonly used for AD Preferred chelator is desferrioxamine (DFO) Other metals associated with AD: aluminum and zinc Conjugated with nanoparticles Easier transport across blood brain barrier

WHAT ARE SOME FUTURE DIRECTIONS THAT CAN BE TAKEN USING NANOTECHNOLOGY?

Thank you! Questions?

References Mattson, Mark. “Pathways Towards and Away from Alzheimer’s Disease.” Nature 430 (2004): Andreasan, Niel and Blennow,Kaj. “CSF biomarkers for mild cognitive impairment and early Alzheimer’s disease.” Clinical Neurology and Neurosurgery 107 (2005): Sunderland, Trey; Hampel, Harald; Takeda, Masatoshi; et.al. “Biomarkers in the Diagnosis of Alzheimer’s Disease: Are We Ready?” Journal of Geriatric Psychiatry and Neurology 13 (2006): Liu, Gang et al. “Nanoparticle Iron Chelators: A new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance.” Neuroscience Letters 406 (2006): Hartig, Wolfgang, et.al. “Electron microscopic analysis of nanoparticles delivering thioflavin-T after intrahippocampal injection in mouse: implications for targeting β-amyloid in Alzheimer’s disease.” Neuroscience Letters 338 (2003): Georganopoulou, Dimitra G., et al. “Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer’s disease.” Proceedings of the National Academy of Sciences 102 (2005): Keating, Christine D. “Nanoscience enables ultrasensitive detection of Alzheimer’s biomarker.” Proceedings of the National Academy of Sciences 102 (2005):