• Alzheimer’s disease is the most common form of dementia.
• Progressive disease that destroys memory and other important mental
• Brain cell connections and the cells themselves degenerate and die.
15. Amyloid precursor protein (APP), presenilin (PSEN1) & PSEN2 genes encode APP
metabolism and Aβ generation.
Overexpression of APP causing cellular and molecular alteration.
β-site amyloid precursor protein cleaving enzyme(BACE1) involved in the cleavage
siRNA - APP targeted gene therapy
CRISPR-Cas9 suppress Aβ associated pathway
16. GENE THERAPY
Apolipoprotein E (APOE) transporter of lipids.
APOE2, APOE3 and APOE4 which carries different risk percentage and differs due
to presence of cysteine(112) or arginine(158) .
APOE4 which increase levels of amyloid while APOE2 has a lower amyloid
Increase the expression level of APOE2 which prevent Aβ deposition.
22. Aβ-TARGETING STRATEGIES
• APP processed by α-secretase within Aβ sequence and generate soluble neurotrophic
• Accumulation of Aβ in brain leads to oxidative stress, neuronal dysfunction.
• Secondary prevention of AD can be made by:
Decreasing the production of Aβ
Stimulation of clearance of Aβ formed
Prevention of aggregation of Aβ into amyloid plaques
23. • Decreasing Aβ neurotoxicity or inhibiting its aggregation have therapeutic
• β-sheet breaker iAβ5p, which showed improved spatial memory and decreased
amyloid plaque deposits (Phase 2).
• Upregulation of α-secretase activity which decrease the amount of APP.
• Deprenyl, increase α-secretase activity by promoting ADAM10 and PKC.
24. β-SECRETASE INHIBITORS
BACE1 inhibitor Lowering of brain Aβ40 and Aβ42.
Decreased APPβ and an increased sAPPα secretion.
KMI-429 reduce Aβ production (Phase 2).
BMS-299897 and MRK560 is a γ-secretase inhibitors (Phase 1 & 3).
γ-secretase modulators, shifting the γ-secretase cutting point to produce shorter,
non-toxic Aβ fragments.
25. PREVENTION OF PHOSPHORYLATION OF TAU
Phosphorylation of tau is controlled by different kinases and phosphatases.
The protein phosphatase (PP)-2A increase dephosphorylation of tau.
Cyclin-dependent kinase-5 (CDK5) and Glycogen synthase kinase (GSK)-3β which
phosphorylate tau in AD.
AF267B – inhibit GSK-3β
• Current therapies providing temporary improvement and reducing the rate of
• Gene therapy appear is a alternative therapeutics strategy.
• Identifying potential therapeutic compounds.
Hong-Qi Y, Zhi-Kun S, Sheng-Di C. Current advances in the treatment of Alzheimer’s disease:
Focused on considerations targeting Aβ and Tau. Transl Neurodegener. 2012; 1(21): 2-9.
Marei HE, Althani1 A, Suhonen J, Zowalaty1 ME, Albanna ME, Cenciarelli C, Wang T, Caceci T.
Recent perspective about the amyloid cascade hypothesis and stem cell - based therapy in
the treatment of Alzheimer’s disease. FCDR. 2016; 5: 3-33.
Rang HP, Dale MM, Ritter JM, Flower R, Henderson G. Pharmacology: Neurodegenerative diseases. 9th ed.
Edinburg: Elseveir Ltd; 2020.
Standaert DG, Roberson ED. Treatment of central nervous system degenerative disorders. In: Brunton LL,
Chabner BA, Knollman BC. Goodman & Gilman’s The pharmacological basis of therapeutics. 12th
ed. New York: McGraw - hill medical publishers; 2011.
Thoe ES, Fauzi A, Tang YQ, Chamyuang S, Chia YA. A review on advances of treatment modalities for
Alzheimer’s disease. Life Sci. 2021; 276: 1-15.
Tripathi KD. Essentials of medicinal pharmacology. 8th ed. New delhi: Jaypee medical publishers;