SlideShare utilise les cookies pour améliorer les fonctionnalités et les performances, et également pour vous montrer des publicités pertinentes. Si vous continuez à naviguer sur ce site, vous acceptez l’utilisation de cookies. Consultez nos Conditions d’utilisation et notre Politique de confidentialité.
SlideShare utilise les cookies pour améliorer les fonctionnalités et les performances, et également pour vous montrer des publicités pertinentes. Si vous continuez à naviguer sur ce site, vous acceptez l’utilisation de cookies. Consultez notre Politique de confidentialité et nos Conditions d’utilisation pour en savoir plus.
RECENT ADVANCES IN
ALZHEIMER'S DISEASE: CAUSES
Sharad P Patange
M.Pharm 1st year
School of Pharmacy
• family history
• Down’s syndrome
• diet/nutritional supplement intake,
• physical activity level,
• type 2 diabetes,
• alcohol consumption,
• hypertension, smoking
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
Neuronal Plaques in Alzheimer’s Disease
Neurofibrillary Tangles in Alzheimer’s Disease
Plaques and neurofibrillary tangles
From Department of Pathology, Virginia Commonwealth University
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.
b a g g
(1) b-secretase cuts APP protein, giving:
(2) g-secretase cuts this residue, giving:
(not drawn to scale)
(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.
Recent advances in treatment of AD
• Anti-amyloid therapy
• 𝛽-Secretase (BACE1) inhibitor
• γ-Secretase inhibitors (GSI) and modulators
• Kinase inhibitors
• Therapy for mitochondrial dysfunction
• Anticholinergic 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
Newer compounds targeted to anti-
Compound Target/Treatment Current phase
Interrupted at phase I
Phase I (ongoing)
Phase III (ongoing)
Phase III (ongoing)
Phase II (ongoing)
Phase I (ongoing)
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
Nuclear peroxisome proliferator activated receptor
gamma (PPAR𝛾𝛾) functions as a transcription factor
which regulates gene expression, promotes
microglia-mediated A𝛽 endocytosis.
Thiazolidinedione can induce PPAR𝛾𝛾 to inhibit
𝛽-secretase and stimulate ubiquitination to
worsen amyloid burden
γ-Secretase inhibitors (GSI) and
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
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
Therapy for mitochondrial
Latrepirdine (DIMEBON), an antihistamine which
preserves mitochondrial structure and function and
protects against A𝛽𝛽 induced apoptosis is under
Its combination with donepezil is also under
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
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