RECENT ADVANCES IN ALZHEIMER'S DISEASE

RECENT ADVANCES IN ALZHEIMER'S DISEASE
new drug for alzheimer disease

1. Seminar on RECENT ADVANCES IN ALZHEIMER'S DISEASE: CAUSES AND TREATMENT Sharad P Patange M.Pharm 1 st year Pharmacology School of Pharmacy S.R.T.M.U.Nanded

2. Causative factors NON-MODIFIABLE age Genes family history Down’s syndrome MODIFIABLE diet/nutritional supplement intake, physical activity level, type 2 diabetes, alcohol consumption, hypertension , smoking

3. Signs & Symptoms: Memory loss for recent events Progresses into dementia  almost total memory loss Inability to converse, loss of language ability Affective/personality disturbance (fatuous, hostile) Death from opportunistic infections, etc. Confirmation of Diagnosis: Neuronal (amyloid, b amyloid, A b amyloid) plaques Neurofibrillary tangles Brain Atrophy

4. Neuronal Plaques in Alzheimer’s Disease From http://www.rnw.nl/health/html/brain.html

5. Neurofibrillary Tangles in Alzheimer’s Disease From http://www.rnw.nl/health/html/brain.html

6. Plaques and neurofibrillary tangles From Department of Pathology, Virginia Commonwealth University

7. Two Major Hypotheses for AD: b amyloid protein (BAP) v. tau BAPtists : The accumulation of a fragment of the amyloid precursor protein or APP (the amyloid beta 42 residue fragment or Ab-42) leads to the formation of plaques that someone kill neurons. TAUists : Abnormal phosphorylation of tau proteins makes them “sticky,” leading to the break up of microtubules. The resulting loss of axonal transport causes cell death.

8. b a g g APP Protein: (1) b -secretase cuts APP protein, giving: (2) g -secretase cuts this residue, giving: or A b 40 Fragment Soluble A b 42 Fragment Unsoluble, aggregates into plaques b -secretase Pathway: (not drawn to scale)

9. Tau Hypothesis (it’s the tangles, dummy) Ordinarily, the t (tau) protein is a microtubule-associated protein that acts as a three-dimensional “railroad tie” for the microtubule. The microtubule is responsible for axonal transport. Accumulation of phosphate on the tau proteins cause “paired helical filaments” or PHFs (like two ropes twisted around each other) that accumulate and lead to the neurofibrillary tangles (NFT). PHFs are the main component in NFTs. Impaired axonal transport is the probable cause of cell death. Focus on MAPT gene (microtubule-associated protein tau) Not in favor anymore.

10. Recent advances in treatment of AD Anti-amyloid therapy 𝛽 - Secretase (BACE1) inhibitor γ- Secretase inhibitors (GSI) and modulators (GSM) Kinase inhibitors Therapy for mitochondrial dysfunction Anticholinergic therapy

11. Anti-amyloid therapy Anti-amyloid therapy involves the uses of drugs with a different mechanism of actions: enhance the clearance of Aβ; ( ii) Prevent the production of Aβ; (iii ) Inhibit the accumulation of Aβ

12. Newer compounds targeted to anti-beta-amyloid treatment

13. Compound Target/Treatment Current phase ANI-1792 Vaccine-active immunization Interrupted at phase I CAD-106 Vaccine-active immunization Phase I (ongoing) Bapineuzumab Beta-amyloid monoclonal antibody Phase III (ongoing) Solanezumab Beta-amyloid monoclonal antibody Phase III (ongoing) Ponezumab Beta-amyloid monoclonal antibody Phase II (ongoing) Gantenerzumab Beta-amyloid monoclonal antibody Phase I (ongoing)

14. 𝛽 - Secretase (BACE1) inhibitor Beta-site APP-cleaving enzyme 1 (BACE1) is a protease responsible for cleavage of APP, resulting in generation of assembly of neurotoxic irregular A 𝛽. Nuclear peroxisome proliferator activated receptor gamma (PPAR𝛾𝛾) functions as a transcription factor which regulates gene expression, promotes microglia-mediated A𝛽 endocytosis.

15. Thiazolidinedione can induce PPAR𝛾𝛾 to inhibit 𝛽- secretase and stimulate ubiquitination to worsen amyloid burden

16. γ- Secretase inhibitors (GSI) and modulators (GSM) γ- secretase is a transmembrane protease responsible for cleavage of amyloid precursor protein (APP) to produce A β . Different GSIs such as DAPT, L685458 andMRK-560 131have been recently developed. While different (GSM) such as avagacestat (BMS-708163), begacestat and NIC5-15 are under clinical trials

17. Kinase inhibitors The first class of tau inhibitors which helps in targeting tau phosphorylation and reduces tau phosphorylation by decreasing the activity of kinase enzyme. Interaction between glycogen synthase kinase 3 beta (GSK3𝛽𝛽) and protein phosphate 2 (PP2A) augments tau hyper phosphorylation and NFT generation. Lithium, valproate, NP-031112 (NP-12) and epothilone D (BMS-241027) decreases tau phosphorylation and prevent reversed features of tauopathy

18. Therapy for mitochondrial dysfunction Latrepirdine (DIMEBON), an antihistamine which preserves mitochondrial structure and function and protects against A𝛽𝛽 induced apoptosis is under investigation. Its combination with donepezil is also under investigation. AC-1204 is considered to improve mitochondrial metabolism by inducing chronic ketosis, thereby releasing regional cerebral hypometabolism presented in early Alzheimer’s disease, and this agent is also under investigation

19. Anticholinergic therapy Anticholinergic therapy includes administration of cholinesterase inhibitors to treat the cholinergic deficit associated with AD. The drugs include tacrine (COGNEXS), donepezil (ARICEPTS), rivastigmine (EXELON), and galantamine (REMINYLS)

20. Human APP gene Human ApoE gene Human Presenilin gene Animal Models

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