This document discusses Alzheimer's disease and potential drug targets and strategies. It begins by introducing Alzheimer's disease and some of its key characteristics like memory loss and neuronal cell dysfunction. It then discusses amyloid beta and its role in Alzheimer's disease pathology. Several current and potential drug targets are mentioned, like acetylcholinesterase inhibitors and NMDA receptors. The document also discusses using biomarkers from sources like platelets and CSF to aid diagnosis and validate drug targets. Methodologies like proteomics and various assays are mentioned for identifying these biomarkers. Overall the goal is to identify novel targets and strategies to enhance cognition and slow disease progression.

1. DRUG TARGETS AND
DRUG DESIGN
Ms. Sanchi Dua
M. Tech. Biotechnology (2009-11)

2. Introduction: Alzheimer's Disease
• Progressive Neurodegenerative Disorder
• Acute Cognitive Decline
Neuronal
Cell
Dysfunction
Memory
Loss
Poorly
understood

3. Amyloid Beta (Aβ)
Aβ (betaamyloid
peptide)
Hallmark of
Alzheimer's
disease (AD)
Yeast Cells
used to study
harmful
effects

4. Pathological Characterization
• Accumulation of extracellular beta amyloid (Aβ) plaques
• Intracellular tau tangles
• Gliosis
• Neuronal cell death

5. Research Objective
Identify
biomarkers
• Peripheral
Biomarkers
• Blood samples easy
to obtain
Novel cognitive- • Increased Efficacy
and Safety
enhancing
therapeutic
strategies

6. Existing clinical methods of diagnosis
Brain Imaging
Characterizing
fluid biomarkers
Cerebrospinal
fluid (CSF)

7. Blood-based biomarkers
Potential sources
Platelets
Small, anuclear fragments
derived from megakaryocytes in
the bone marrow
Platelets
Respond to
neurotransmitters
Enzymes responsible
for generating the Aβ
peptide.
High concentration of
amyloid precursor
protein (APP)

8. Methodology for identifying Biomarkers
Validation of Cooccurrence of other
pooled analyte
changes consistent
with previous
biomarker studies
Platelet isolation
and membrane
protein enrichment
Quantification of
membrane-enriched
proteome

9. Cognitive Aging
Aging
Cognitive
functions
decline

10. Current drug targets
To improve cognitive function
Inhibit acetylcholinesterase
(AChE)
N-methyl-D-aspartate
receptor

11. Novel cognitive-enhancing therapeutic
strategies
To slow disease
progression in AD patients
To enhance cognitive
function

12. Potential Drug Targets
Metabotropic
glutamate
receptor subtype
5
• Increasing the activation of
mGlu5
Nicotinic
acetylcholine
receptor
• Activation of the α7nAChR
subtype with smallmolecule agonists
M1 Muscarinic
acetylcholine
receptors
• potential to affect multiple
disease pathologies
including amyloid-beta and
phosphorylated tau

13. Potential Drug Targets
• Indirect cholinergic
5Hydroxytryptamine stimulation through
5-hydroxytryptamine
receptors
(5-HT) receptors
6
Norepinephrine
• Noradrenergic
neurons: vulnerable
during aging
Cyclic adenosine
monophosphate
• cAMP signaling is
increased with aging

14. Experimental Techniques
• Immunostaining
• Immunoblot
• Indirect ELISA Assay
• Mass spectrometry (MS)-based proteomics