The document summarizes recent advances in understanding and treating Alzheimer's disease. It discusses both non-modifiable and modifiable risk factors for the disease. The major signs and symptoms include progressive memory loss and cognitive decline. Alzheimer's is confirmed through neuronal plaques and tangles seen in the brain. Recent treatment strategies aim to reduce amyloid plaques through vaccines, antibodies, and inhibitors of beta- and gamma-secretase. Other approaches include tau phosphorylation inhibitors, therapies for mitochondrial dysfunction, and cholinesterase inhibitors. Animal models continue to be important for studying the human APP, ApoE, and presenilin genes involved in Alzheimer's pathology.

1. Seminar on
RECENT ADVANCES IN
ALZHEIMER'S DISEASE: CAUSES
AND TREATMENT
Sharad P Patange
M.Pharm 1st 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, Ab 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
1.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.
2.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.

10. b a g g
APP Protein:
(1) b-secretase cuts APP protein, giving:
(2) g-secretase cuts this residue, giving:
or
Ab40 Fragment
Soluble
Ab42 Fragment
Unsoluble,
aggregates into
plaques
b-secretase Pathway:
(not drawn to scale)

11. Tau Hypothesis
(it’s the tangles, dummy)
1. 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.
2. 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.
3. Impaired axonal transport is the probable cause of cell death.
4. Focus on MAPT gene (microtubule-associated protein tau)
5. Not in favor anymore.

12. 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

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

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

15. 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)

16. 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 A𝛽.
Nuclear peroxisome proliferator activated receptor
gamma (PPAR𝛾𝛾) functions as a transcription factor
which regulates gene expression, promotes
microglia-mediated A𝛽 endocytosis.

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

18. γ-Secretase inhibitors (GSI) and
modulators (GSM)
γ-secretase is a transmembrane protease
responsible for cleavage of amyloid precursor
protein (APP) to produce Aβ .
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

19. 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

20. 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

21. 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)

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

23. THANK
YOU