This Slide describes progression of alzheimer disease and the changes that occurs in alzheimer disease. Also it describes how the disease progress to different parts of brain and which different part of brain are involved in it. It is made by Gopal Agarwal, Ph.D Research Scholar, NIPER-Ahmedabad

1. BY
Gopal Agarwal (Ph.D student@ NIPER-A)
gopalniperbt@gmail.com

2. AD is a progressive and irreversible neurodegenerative disease characterized by
progressive loss of memory and cognitive function
Risk factors for AD include
 old age
 positive family history
 unhealthy life style
 consumption of high fat diet
 Exposure to toxic environment
 production of reactive oxygen species
 disruption of calcium homeostasis
 activation of Wnt pathway
 excitotoxicity
 activation of apoptotic pathways
 neuronal degeneration
 neurotransmitter deficits

3. Clinically, AD is characterized by deterioration of memory and cognitive
function, progressive impairment of activities of daily living, and several
neuropsychiatric symptoms.
Neuropathologically, AD is characterized by the accumulation of beta-
amyloid (Aβ) protein that forms plaques and tau protein phosphorylation
that promote the formation and deposition neurofibrillary tangles (NFT)
According to Aβ hypothesis the accumulation of senile plaques and
neurofi brillary tangles is accompanied by neuronal atrophy and
progressive synaptic failure, which initially appears in the entorhinal
region and the temporal lobe, before progressing to the limbic system
and subsequently to major areas of the neocortex, severely damaging
the brain

4. Characteristics: NFT and amyloid plaques in AD
(2016). How Does Alzheimer’s Begin and Who Gets It? Alzheimer’s Turning Point, Springer: 1-20.

5. Progression of tau spreading in Brain
(2015) "Tau imaging: early progress and future directions." The Lancet Neurology.

6.  severe atrophy
 Hippocampus
 Ventricle enlargement
Progressive degeneration in AD
(2016). How Does Alzheimer’s Begin and Who Gets It?
Alzheimer’s Turning Point, Springer: 1-20.

7. Difference between Aβ and amyloid
• Aβ is a normal peptide generated throughout life, while
amyloid plaques are a neuropathological hallmark of AD
• Aβ production and secretion is stimulated by synaptic
activity, the most unique and normal function of the nervous
system
• Generation of the small Aβ peptide (up to 42 or 43 amino
acids long) is not inherently toxic and might even have a
physiological function
• Amyloid plaques are composed of a multitude of highly
aggregated Aβ fibrils and they represents an abnormal
pathological lesion
(2015). "β-amyloid Peptides and Amyloid Plaques in Alzheimer’s Disease." Neurotherapeutics

8. Two hypothesis that explain the spread of
amyloid plaques
a) Pathogenic spread
Hypothesis
b) Selective vulnerability
Hypothesis
(2016). "A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration." Nature Reviews Neuroscience

9. • Both pathogenic spread and selective vulnerability can account for the
sterotypical spatial distribution of protein aggregates.
• ‘pathogenic spread’ hypothesis : aggregates generated in one brain
region physically move from neuron to neuron and thus spread into
connected brain regions.
• “selective vulnerability” hypothesis : in response to certain adverse
conditions (such as external stress), protein aggregation is initiated in
a subset of neurons that are particularly vulnerable to the adverse
stimuli. Protein aggregates appear first in the cells most susceptible to
the adverse conditions, and with time aggregates emerge in less-
susceptible cells. This hypothesis also supports the idea that disease
pathogenesis may spread trans-synaptically; however, it suggests that
this is mediated by the spread of diffusible metabolic factors that
result in the transduction of the effects of the adverse conditions to
a neighbouring neuron, rather than by direct physical transfer of
protein aggregates.
• It is important to note that these two possibilities are not
mutually exclusive and that a combination of both mechanisms may
occur.

10. How does plaques spread from one neurons
to another
1) Exosomes
2) TNT: tunnelling
nanotubes (TNTs)
3) involves the release and
uptake of the naked protein
4) proteins are released as a
secondary effect of synaptic
or cellular compromise
(2016). "A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration." Nature Reviews Neuroscience

11. MRI and PET imaging of tau and
Aβ with 1⁸F-T807 and 11C-PiB
in healthy controls, a patient
with
mild cognitive impairment, and
a patient with Alzheimer’s
disease
a)
b)
c)
d)
a) 75-year-old;Normal;Amyloid–MMSE 30
b) 79-year-old;Normal;Amyloid + MMSE 29
c) 70-year-old;MCI;Amyloid + MMSE 26
d) 68-year old; AD dementia; Amyloid+ MMSE
23
MRI Tau Aβ
(2015) "Tau imaging: early progress and future
directions." The Lancet Neurology.

12. Therapy for AD
• Beta Secretase inhibitor
• Gamma secretase modulator
• Alpha secretase stimulator
• Inhibition of Aβ aggregation
• Immunotherapy against Aβ aggregation
• Antioxidant therapy
• Acetylcholinesterase inhibitors
• Glutamatergic system modifiers for AD therapy
• Anti-inflammatory agents for AD therapy
• 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) for AD therapy
• Insulin for AD therapy

13. Recent Research in Alz.
• Potential Role of Aminoprocalcitonin in the Pathogenesis of Alzheimer Disease
(http://dx.doi.org/10.1016/j.ajpath.2016.06.006)
• Probing gamma-secretase–substrate interactions at the single amino acid residue
level (10.15252/embj.201694978)
• Monoaminergic Neuropathology in Alzheimer's disease
(http://dx.doi.org/doi:10.1016/j.pneurobio.2016.04.001)
• Alzheimer’s disease via enhanced calcium signaling caused by the decrease of
endoplasmic reticulum–mitochondrial distance
(http://dx.doi.org/10.1016/j.mehy.2016.01.022)
• Age and Alzheimer’s disease gene expression profiles reversed by the glutamate
modulator riluzole (10.1038/mp.2016.33)

14. -By-
Gopal Agarwal,
Ph.D Research Scholar,
Dept. of Biotechnology,
National Institute of Pharmaceutical Education and
Research-Ahmedabad,
Gandhinagar
gopalniperbt@gmail.com