Alzheimer’s is a progressive disease. Due to minimal repair and regeneration capacity of brain tissue, early and precise diagnosis is needed. The earlier we stop the pathogenic process, less the patient will remain symptomatic.
Nanodiagnostics for Alzheimer’s Disease
Current diagnostic methods suffer from limitations such as low sensitivity, accuracy, dependence upon brain reserves and severity of disease. These limitations make timely therapeutic intervention of AD difficult.
Nanotechnology has potential to detect ultra low concentration of bio-markers. A bio-barcode assay for detection of ADDL was developed by using magnetic microparticles conjugated with monoclonal antibody against ADDL, and gold nanoparticles conjugated with polyclonal antibody against ADDL along with DNA strands. This sandwich assay showed sensitivity of several orders of magnitude higher than Enzyme Linked ImmunoSorbent Assay (ELISA) technique.
Another diagnostic approach makes use of optical property (Localized surface Plasmon resonance, LSPR) of triangular silver nanoparticles. LSPR depends upon the size, shape and local external dielectric environment of nanoparticles, and it very sensitive to change in properties and environment. Binding of ADDL on anti-ADDL antibody conjugated to triangular silver nanoparticles results in change in its refractive index which can be manifested by change in LSPR in UV-visible spectroscopy.
These methods are less expensive, faster, and efficacious than current assays, but they require sampling of CSF which is invasive and hard to obtain. Therefore there is need to develop assays using blood samples rather than CSF.
Nanotechnology based therapy for Alzheimer’s Disease:
Treatment of AD is hindered due to presence of Blood brain barrier (BBB) and Blood-cerebral spinal fluid barrier (B-CSFB), characterized by presence of tight junctions, efflux transporters (P-gp, MDR1), high interstitial pressure, high electrical resistance, thus making it difficult for a molecule to enter the brain. Nanoparticles offer great potential in drug delivery across brain due to small size, ease of surface modification (active and passive targeting). Moreover, nanoparticles can also be used as multifunctional platform for diagnostic, treatment and monitoring treatment of diseases. Nanoparticles have been known to cross BBB and B-CSFB by conjugation with targeting ligands (angiopep-2, transferrin) or with surfactants (Polysorbate 80).
Nanotechnology based intervention for treatment and prevention of AD can be divided into three categories :
- Neural regeneration
- Drug delivery systems
In AD, formation of plaques and tangles results in disruption of communication and transport between neurons, this leads to their degeneration. Therefore, protection of neurons from cellular toxicity is the rational approach for treating AD. Oxidative stress and amyloid induced toxicity are two basic processes in AD pathogenesis.
Accumulation of free radicals causes oxidative stress leading to formation of NFT and Aβ oligomers, triggering neural degeneration. Nanoparticles have potential to act as free radical scavengers or as the carriers of free radical scavengers for efficient transport into the brain.
Buckminsterfullerene (C60) has potent anti-oxidant activity, but it is insolubility in water limits its use as a scavenging agent. Modified form of C60 (carboxylic acid-functionalized C60, carboxyfullerenes, and/or hydroxyl fullerenes, fullerenols) are water soluble and they were able to reduce oxidative stress and neurotoxicity induced by amyloid-beta peptide in cultured cortical neurons.
It includes protection from toxicity induced by oligomeric and ﬁbrillar (polymeric) Aβ species by preventing the assembly of Aβ monomers, and breakdown or resolubilization of already formed oligomers or ﬁbrillar Aβ.
An anti-assembly strategy was developed by using an amphipathic cholesterol bearing pullulan (CHP) nanogel. Pullulan is water soluble polysaccharide and cholesterol contributed as hydrophobic moiety for formation of amphipathic CHP nanogel. These nanogels were 20-30 nanometers in size and mimicked molecular chaperons which are involved in folding and unfolding of proteins. The nanogel particles were able to incorporate Aβ monomers (6-8 monomers per nanogel particle) and inhibited the assembly of Aβ. This technique prevents assembly at the monomer level, thus it prevents Aβ from oligomerization also.
Resolubilization of fibrillar amyloid deposits was demonstrated by using thermal energy. Thermal energy was generated by using gold nanoparticles and low energy microwave radiations, heat generated could selectively dissolve fibrillar amyloid deposits. The microwave energy used was very lower as compared to that used in mobile phones. Dissolution of amyloid deposits might result in possibility of forming oligomers following breakdown of the fibrillar species, which are neurotoxic as well.
Brain cells have little regeneration capacity, and the loss of brain cells due to amyloid and oxidative stress induced toxicity, makes the damage caused by AD irreversible. It is possible to regenerate brain cells by using neural stem cells, which can differentiate into neurons, astrocytes, and oligodendrocytes. Neural stem cells (NSC) therapy involves proliferation of NSC in laboratory to sufficient volume which can initiate the process of tissue regeneration upon injection into the body. But stem cells cultured on plastic surfaces can differentiate into other cell types and thus lose their regenerative capacity. Recently, a novel surface patterned with an ordered arrangement of nanoscale pits was used as substrate for allowing stem cells to proliferate while also maintaining their stem cell characteristics for long period of time. Such nano-patterned surfaces may provide a basis for large-scale culture of stem cells, enabling therapies for various diseases, including AD and Parkinson’s.
Nanomediated drug delivery:-
Penetration of drug into brain is hindered by presence of BBB and B-CSFB, only a small class of molecules can penetrate the brain. Nanotechnology has potential to improve the efﬁcacy of therapeutic agents against CNS diseases including AD by facilitating their delivery across BBB. Encapsulation and conjugation of therapeutic molecules with nanoparticles result in decreased toxicity, increase in therapeutic index, improved pharmacokinetic and pharmacodynamic properties. Surface of nanoparticles can also be modified to avoid uptake and clearance by MPS, due to the small size of nanoparticles, they can penetrate deep into tumors as tumor blood vessels are leaky. Binding of targeting moieties (transferrin, folic acid etc.) to nanoparticles allows specific targeting of cells expressing the receptors for these ligands.
Recently selective targeting of fibrillar Aβ was demonstrated by intracerebral injection of core-shell nanoparticles in mice with age dependent β-amyloidosis. The core-shell nanoparticles were of 90-100 nm in size, and composed of polystyrene core and PBCA [poly (butyl-2-cyanoacrylate)] shell. The enzymatic degradation of PBCA shell allowed controlled and long-term drug delivery in the brain.
Metal chelation therapy is used to reduce the cellular oxidative stress caused by accumulation of metals like iron in the brain. Metal chelating compounds attenuate the toxic effects of metals. A chelator nanoparticle system (CNPS) was developed, in which Desferrioxamine (chelating agent to remove excess iron) was conjugated to nanoparticle surface to chelate iron. Chelating effect of desferrioxamine was retained after its conjugation with nanoparticles. The iron chelated CNPS was able to traverse the BBB in the reverse direction too.
Nazem, A., & Mansoori, G. A. (2008). Nanotechnology Solutions for Alzheimer ’ s Disease : Advances in Research Tools , Diagnostic Methods and Therapeutic Agents, 13, 199–223.
Image credit: http://www.technologytell.com/gadgets/99069/nanotech-breakthrough-could-make-diseases-3-million-times-easier-to-detect/
- A New Spinal Fluid Test Provides Hope for Early Alzheimer’s Warning and Diagnosis
- Avid Radiopharmaceuticals PET SCAN based Diagnostic Test for Alzheimers Approved by FDA Committee
- List of Alzheimer’s Disease Clinical Trials, New Treatments, Research Investigators and Institutions
- Detecting Cancer Dust/Microvesicles In Blood To Diagnose Brain Cancer Using Novel Nanotechnology and NMR Based Device
- Diabetes and Alzheimer’s Disease Could be Treated with One Drug, Metformin