Alzheimer is the most neurodegenerative disorder in the aged people. It is characterized by senile, accumulation of amyloid plaque, neurofibrillary tangle and progressive decline in brain memory cells. Alzheimer disease is associated with inflammatory response, synaptic damage and mitochondrial dysfunctions which are a prominent and early feature of Alzheimer disease.

1. Done by: Rana Abdulnaser Alhakim
‫الحكيمي‬ ‫عبدالناصر‬ ‫رنا‬
Decreases Expression of PGC-1α
in the Alzheimer Disease Brain
Impaire Mitochondrial Function
and Distribution

2. Introduction

4. APP
Amyloidogenic pathway Non- amyloidogenic pathway
Figure (1(

5. Peroxisome proliferator-activated
receptor c coactivator 1 α (PGC1(
 PGC1 α is a positive regulator of mitochondrial
biogenesis and respiration, adaptive thermogenesis,
gluconeogenesis as well as many other metabolic
 The expression of PGC1α is highly inducible by
physiological cues, including exercise, cold and fasting.
 A central function of PGC1 α that is intimately linked to
mitochondrial biogenesis is the detoxification of reactive
oxygen species (ROS) by regulating the expression of
numerous ROS-detoxifying enzymes.

6. Figure (2(

7. Some previous studies studied the affect
of Alzheimer disease on mitochondrial
function
 Mitochondrial dysfunction in AD may involve the action
of APP and Aβ, as they were reported to target the
mitochondria and cause mitochondrial dysfunction
(Caspersen et al., 2005; Devi et al., 2006; Manczak et al.,
2006).
 AD pathology is associated with decreased expression
and activity of proteins involved in mitochondrial
bioenergetics and mitochondrial dysfunction (Yao et al.,
2009).

8. Materials & Methods

9. A human neuroblastoma
M17 cell line ( this cell
lines expresses human
Swedish mutation APP695
or control).
To study affect of Aβ
on PGC-1α expression
Human neuroblastoma cell
line SH-SY5Y control (SH-
SY5YCon) and SH-SY5Y cells
in which Fe65 was knocked
down (SH-SY5Y-Fe65KD).
To study affect of AICD
on PGC-1α expression
(AβPP) transgenic mice
(Tag2576 line) and the non-
transgenic wild-type (WT) .
To study affect of Aβ ON
mitochondrial
distribution & The affect
of glucose on
amyloidogenesis
DKO MEFs reconstituted with
empty expression vector
pcDNA3.1 (PS1/2) or with
pcDNA3.1 vectors directing
the expression of WT human
PS1 or one of the following
PS1- FAD mutations: P267S,
A285V, T354I, or L392V.
To study affect of γ-
secretase on PGC-1α
expression
 Fetal bovine serum.
 Penicillin streptomycin.
 Humid incubator with
CO2 at suitable T
 SH-SY5Y cells, mice (Tag2576
line), & DKO MEFs cell were
incubated with the γ-secretase
inhibitor and AICD peptide, BrDU,
Heavy & light amino acids
respectively.
CULTURE MEDUIM

10. Immunoblot analysis: Used
to detect expression level of
proteins (PGC-1α, BACE-1, γ-
secretase, α- secretase, Aβ,
presenilin(1,2), AICD and NRF.
Real time PCR & microarray:
Used to sequence RNA and detect
expression level of mRNA .
Statical
Analysis

11. Results & discussion

12. Why PGC-1α expression was decreased in
AD?
mutation in γ-
secretase
AICD
Mutation in
APP gene or
regulatory
genes
AβGlucose FOXO3a
dementia

13. PS1-FAD mutations decreased PS1’s ability
to enhance PGC-1a mRNA expression & AICD
increase PGC-1α expression
Figure(3): The effect of PS1 and AICD on the expression of PGC-1a and PGC-1a
target genes.

14. γ- Secretase regulate PGC-1α
expression
PGC-1α gene
Figure (4(

15. Mitochondrial biogenesis protein are
reduced in hippocampal tissues from AD
patient
Figure(5): (PGC-1α
) expression in the Alzheimer disease (AD) brain are determined in
presence of both AD β-amyloid (Aβ) neuropathology (a) and dementia(b).
)a( )b(
AβControl
CDR

16. Reduced mitochondrial biogenesis causes
mitochondrial dysfunction in PGC-1a
knockdown cells
Figure (6): Down-regulation of PGC-1a affect on expression of mitochondrial
biogenesis proteins and mitochondrial content in M17 cells.

17. Mitochondria with new DNA synthesis
exist largely in cell bodies of AβPP
neurons.
Figure(7): # of mDNA synthesis in cell body and neurite in both wild type neuron
cells and AβPP neuron cells, BrdU staining are used to follow the mDNA.
(

18. How can Aβ decreases PGC-1α
expression?
Poly(ADP-ribose)
polymerase-1
(PARP
SIRT
PGC
-1α
Aβ ROS
ATP
PKA
CREP
AMPK
Figure (8(

19. How can dementia decreases PGC-1α
production?
FOXO3a ROS PGC-1α
IMPAIRED GLUCOSE
METABOLISM
Aβ Dementia
Figure (9(

20. Increased concentration of glucose
inhibits (PGC-1α) expression and promotes
β-amyloid (Aβ) generation in Tg2576
neurons
Figure(10): concentration of PGC-1α and Aβ in high concentration of glucose and the
affect of PGC-1α concentration on α secretase activity.

21. Conclusion
 Decrease expression of PGC-1α contributes to
mitochondrial dysfunction and affect on mitochondrial
distribution.
 PGC-1α activate α- secretase and suppress β- secretase
genes, so decreases in PGC-1α lead to reveres this
mechanisms and increase A β production
 Increase PGC-1α production may represent a potential
pharmacologic approach for the treatment of AD.

22. REFRENCES
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24. THANK YOU
FOR
YOUR
ATTENTION
ANY QUESTION?