This presentation is mainly focused on an Amyloid-beta cascade hypothesis and its impacts, causing mitochondrial dysfunction.

1. Symptoms:
Apathy and depression at the early stage.
Memory loss, confusion with time or place.
Trouble understanding visual images and spatial relationships.
Problems and language, disorientation, and behavioral issues
after the disease becomes more severe.
Mitochondrial dysfunction and nerve cell apoptosis.
What is AD?
Alzheimer’s disease is a neurodegenerative disease. Thus, it
gets worse over time with decline of brain ability.
Hyper-phosphorylated tau protein aggregates are considered
as a orientation of AD.
On the other hand, Amyloid-beta deposits are also
considered as a potent reason for AD (Amyloid-beta cascade
hypothesis)
Amyloid-beta cascade
hypothesis
Many researches indicate that
Amyloid beta oligomers eventually
cause damages in plasma membrane
proteins and cause various
symptoms such as mitochondrial
dysfunction.
Amyloid-beta
Aβ is a derivative of APP (Amyloid precursor
protein). Most of the time, α-secretase cleaves
APP. However, if β-secretase cleaves the APP,
amyloid beta proteins are produced. When Aβ
are deposited, they form an Aβ oligomers and
the deposited form of these oligomers are
fibrils. At first, fibrils thought as a potential
amyloid causing AD, but they are insoluble,
while amyloid oligomers are soluble and able
to across the cells easily. Thus amyloid-beta
oligomers are the potential target for the AD
cure.
People diagnosed AD.
In America(in 2020), estimated
number of Americans diagnosed
Alzheimer’s disease are 6 million.
Most of them, 5.8 million people
are elderlies(over 65) while there
are some exceptional young
patients.
In world (in 2015). Estimated
number of people with AD is
nearly 50 million people, whereas
25% of them actually diagnosed.
To stabilize the [Ca 2+]cyt,
mitochondria takes Ca2+
into its matrix via
mitochondrial Ca2+
uniporter, MCU. However,
this gradually leads into
reactive oxidative species.
Subsequently, ROS
production inhibits ATP
synthesis with
mitochondrial
dysfunction.
MCU
NMDA
NMDAR, N-methyl-D-aspartate receptor is
a protein channel that uptakes the Ca2+
ions from ECM into cytoplasm (facilitated
diffusion) after its activation. Amyloid beta
oligomers attach to this protein and force
to activate.
mGluR5
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+Ca2+
α-secretase
translation
Potential treatment
The most effective treatment recent days(accepted to use) is MCU blocker
drugs. MCU blockers prevent radical [Ca2+]cyt and [Ca2+]mit. Therefore,
mitochondria’s cellular respiration activity can be stable.
One of the uprosen drug was lanabecestat, a β-secretase inhibitor.
AstraZeneca and Eli Lilly codeveloped but failed at phase II/III clinical
trial. However, β-secretase inhibitor is still left as a potential
treatment.
Another possible treatment is antibodies attach to Amyloid-beta
42(most common form) oligomers or antibodies that attach to the
NMDA protein so that Amyloid beta proteins cannot have any
specific epitopes to NMDA.
Amyloid-
beta
mGluR5 is a Gprotein-couple receptor, when it is
activated, amount of α-secretase translation
assisted by FGMR protein is decreased. At the
same time, this induces more amyloid-beta
production with induced sAPPα secretion: a
positive feedback loop.

2. Citation
1) https://www.nature.com/articles/aps201728
2) https://www.nature.com/articles/s41467-020-16074-2
3) https://www.nature.com/articles/s41467-019-11813-6
4) https://pubmed.ncbi.nlm.nih.gov/7695913/
5) https://www.sciencedirect.com/science/article/pii/S0143416012000541
6) https://pubmed.ncbi.nlm.nih.gov/20061018/
7) https://pubmed.ncbi.nlm.nih.gov/1608449/
8) https://pubmed.ncbi.nlm.nih.gov/27295499/
9) https://pubmed.ncbi.nlm.nih.gov/31686033/
10) https://pubmed.ncbi.nlm.nih.gov/19584430/
11) https://pubmed.ncbi.nlm.nih.gov/9717197/
12) https://www.pnas.org/content/102/48/17342
13) https://www.pnas.org/content/90/5/2092
14) https://www.alzheimers.net/resources/alzheimers-statistics
15) https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12068
16) https://www.alz.org/alzheimers-dementia/10_signs