**4. Generation of Aβ**

Bad

Bcl-xL

Thr 308 P

6

PDK1

Akt

NF-κB

5

MnSOD CuSOD Bcl-2 Bcl-xL

Ser 473 P

3

PIP<sup>2</sup> PIP<sup>3</sup>

Caspase- 9

4

CREB

Apoptosome

**Figure 2.** Insulin receptor binding of insulin triggers a complex signaling cascade (in blue) leading to activation of the serine/threonine kinase Akt. Upon binding of insulin, insulin receptors are autophophorylated and subsequently bind IRS proteins. IRS proteins are then phsophorylated by activated insulin receptors and complex with PI3K resulting in PI3K activation. Activated PI3K produces phospholipid secondary messengers by catalyzing the conversion of phos‐ phatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 messengers activate PDK1 which phosphorylates Akt at Threonine 308. Akt is further activated by phosphorylation at Ser 473 by mammali‐ an target of rapamyicin 2 (mTORC2). Targets of activated Akt include pro-apoptotic mediators (in red) as well as prosurvival machinery (in green). Loss of insulin signaling (at sites labeled with numbers 1-6 in purple) allows FoxO and p53 transcription factors to remain active and (1) transcribe genes for pro-apoptotic proteins such as BIM, BAX and FasL. Akt inhibits the activity of GSK-3β that, when active, (2) causes increased amyloidogenic processing and hyper‐ phosphorylation of tau. Other pro-apoptotic proteins inhibited by Akt include (3) caspase-9, which forms an apoptotic structure known as the apoptosome, and (6) Bad, which blocks activity of the ant-apoptotic protein Bcl-xL. Pro-survival modulators regulated by Akt include CREB and NF-κB. Reduction of CREB transcriptional activity as a result of a loss of insulin signaling leads to (4) decreased BDNF and Bcl-2 expression while inhibition of NF-κB leads to (5) reduced ex‐

pression of anti-oxidants such as MnSOD and CuSOD as well as anti-apoptotic Bcl-2 family members.

PI3K IRS P

1

2

mTORC2

GSK-3β

P53 FoxO

422 Understanding Alzheimer's Disease

FasL

BIM

Aβ

Tau <sup>P</sup>

BDNF

Bcl-2

BAX

insulin

P

IRS

IRS P **Background** Aβ is a small peptide 38-43 amino acids in size long believed to have a major role in neurodegeneration and pathology of AD (for review see [299]). In sporadic AD (sAD), which accounts for over 90% of AD cases, Aβ's role in pathogensis is still under heavy investigation. The cause of familial AD (fAD), however, has been linked to 3 mutations involved in Aβ processing; presinilins 1 and 2 (PS1/PS2), which are part of Aβ producing complexes, and amyloid precursor protein (APP) from which Aβ is derived [300]. Successive cleavages of APP by β- and γ-secretases produce toxic Aβ peptides (for review see [301]) while cleavage by αsecretase produces the neuroprotective product Secreted APP alpha (sAPPα) [302].

While the physiological role of APP remains unknown, it has been suggested that APP plays a part in neurite outgrowth, synaptogenesis, neuronal trafficking along the axon, transmem‐ brane signal transduction, cell adhesion and calcium metabolism, all of which still require in vivo evidence (for review see [303]). APP concentrations are elevated in the brain during the prenatal period in mice which implies a role of APP in brain development [304]. In the adult brain, APP is expressed in regions of synaptic modification [304] and has been shown to increase hippocampal neuronal response to glutamate [305].

APP belongs to a family of transmembrane proteins that includes APP-like protein 1 and 2 (APPLP1/APPLP2). All APP family members are processed in a similar fashion by α, β, and γ secretases [306-308], however the Aβ domain is unique to APP. Three isoforms of APP have been identified consisting of 695, 751, or 770 amino acids which arise from alternative splicing of the same gene located on chromosome 21 [309]. APP 751 and APP 770 are expressed in most tissues and contain a 56 amino acid Kunitz Protease inhibitor (KPI) domain not found in the neuron specific 695 isoform [310, 311]. mRNA levels of the 2 KPI containing isoforms are elevated in AD brains and are associated with Aβ deposition [312].

Synthesis of APP occurs in the endoplasmic reticulum where it is then transported through the golgi apparatus to the trans golgi network where the highest concentrations of APP are found in neurons [313-315]. From there, APP can be transported in secretory vesicles to the cell surface where α-secretases are located, however, Aβ production occurs within the trans golgi network where γ-secretase complexes are thought to reside [315-318].

**APP cleavage** Aβ generation requires cleavage of APP by β-secretase which has been inden‐ tified to be BACE1 [319-322]. Several studies have found that regions of the brain affected by AD have elevated BACE1 activity and levels [319, 320]. Once identified, BACE1 became a popular therapeutic target for AD treatment. However, BACE1 knockout mice have shown reduced survivability after birth and were smaller than wild-type littermates [323]. BACE1 knockouts also present with hyperactive behavior [323] and other abnormalities such as hypomyelination of peripheral nerves, reduced grip strength and elevated pain sensitivity [324].

APP cleavage by BACE1 results in two fragments: sAPPβ and Beta Carboxyl Terminal Fragment (βCTF) [301, 325]. sAPPβ has been identified as a ligand for Death Receptor 6 which mediates axonal pruning and neuronal death [326]. The remaining βCTF can be cleaved by γ secretase to produce Aβ [301]. γ-secretase is a complex composed of at least 4 components: PS1 or PS2, nicastrin, anterior pharynx defective-1 (APH-1) and presenilin enhancer-2 (PEN-2) [327, 328]. βCTF cleavage by γ secretase produces either Aβ40 or Aβ42 peptides [301]. Aβ42 is the more hydrophic and amyloidogenic of the 2 species and makes up about 10% of Aβ produced [329]. An increased Aβ42/Aβ40 ratio has consistently been shown in fAD patients suggesting that Aβ42 is critical to AD pathogensis [330, 331].

in hyperinsulinemic conditions as IDE binding sites are overloaded with excess insulin and made unavailable for Aβ [115]. Lack of insulin signaling and IDE availability allows for continued accumulation of Aβ, further depression of insulin signaling systems, increased

2

INSULIN RESISTANCE IN THE BRAIN

GSK-3<sup>β</sup> IDE

**Figure 3.** T2DM can lead to the induction of insulin resistance in the brain. (2) Reduction of insulin signaling in the brain increases the activities of GSK-3β and β secretases which (3) increase levels of toxic Aβ oligomers. Furthermore, (4) insulin resistance lowers the expression of Aβ-degrading IDE. (5) Reduced IDE then leads to increased Aβ and (6) accumulation of Aβ oligomers. T2DM also causes (7) hyperinsulinemia which exacerbates IDE deficiencies because (8) excess insulin occupies IDE binding sites rendering them unavailable for Aβ. The increased amyloidogenic processing that occurs in insulin resistance combined with decreased Aβ clearance by IDE results in a deleterious positive-feed‐ back cycle as (9) Aβ oligomers contribute to insulin resistance in the brain. As Aβ levels continue to rise, insulin resist‐

By 2050 it's estimated that over 100 million people worldwide will have AD [344] causing a substantial financial burden for health care systems. In that same time span, the annual cost of treating AD is predicated to exceed \$1 trillion in the United States alone [345]. These crippling social and economical effects place increased priority for advancement of AD

6

β – Secretase

3

Aβ Oligomers 9

Alzheimer's Disease and Diabetes http://dx.doi.org/10.5772/54913 425

neuronal vulnerability and further neurodegeneration.

1

8

ance worsens leading to further production of the toxic peptide.

4

5

Aβ

7

T2DM

HYPERINSULINEMIA

**6. Conclusion**

research.
