Download altered expression of insulin receptor in hippocampus of

“AMYLOID CASCADE” HYPOTHESIS: IS IT TRUE FOR SPORADIC
ALZHEIMER’S DISEASE?
M. Šalković-Petrišić, E. Grünblatt, J. Osmanović, S. Hoyer, P. Riederer
Huge progress in understanding and treating of Alzheimer's disease (AD) has
started whith the era of AD modeling. However, experimental model that
recapitulates all aspects of Alzheimer's disease (AD) has not yet been produced
although various transgenic mouse lines have been designed that offer relatively
faithful reproductions of some of the main neuropathologicall features; extracellular
senile plaques composed of unsoluble amyloid beta (Aβ) fibrilles, and intraneuronal
neurofibrillary tangles composed of hyperphosphorylated form of microtubule
associated protein tau. Currently, the leading hypothesis assumes that pathological
assemblies of Aβ are the cause of all forms of AD, whereas other neuropathological
changes are downstream consequences of pathological Aβ accumulation. However,
this hypothesis fits only to the familial, early onset type of AD caused by mutations
in three particular Aβ-related genes, while the great majority of AD patients have
sporadic late-onset type of disease (sAD) with age and several susceptibility genes as
risk factors. In line with the brain insulin dysfunction found post-mortem in sAD
patients, streptozotocin-intracerebroventricularly treated rats (STZ-icv) have been
recently proposed as an experimental model for sAD because STZ is a drug
selectively toxic for insulin producing/secreting cells. Central, icv application of STZ
is associated with progressive deficits in learning and memory, decrement in
cholinergic transmission and decreased glucose and energy metabolism in the brain.
To further characterize this model we investigated the brain insulin system and
influence of its dysfunction on tau protein and amyloid beta (Aβ) peptide following
STZ-icv administration.
Gene expression of insulin and insulin receptor (IR), alterations of IR-beta subunit,
IR tyrosine kinase (TK) activity, expression of protein kinase B (Akt/PKB),
glycogen synthase kinase 3 (GSK-3) and tau protein were measured by RT-PCR,
ELISA, TK assay and Western blot in frontoparietal cortex (CTX) and hippocampus
(HPC) of adult STZ-icv (1 mg/kg) treated rats. Aβ aggregates were visualised by
Congo red staining. Cognitive deficits were measured in Morris Water Maze Test.
Data were analysed by Cruscal-Walles ANOVA and Mann-Whitney U test (P<0.05).
Expression of insulin-1 (HPC) and -2 (CTX) and IR mRNA (CTX, HPC) was
decreased. Phosphorylated IR-beta subunit content was increased (CTX) and TK
activity increased (HPC). Akt/PKB and phosphorylated/non-phosphorylated GSK3α/β ratio were decreased (HPC) GSK-3-related hyperphosphorylation of tau protein
(HPC) and Aβ aggregates in meningeal capillaries were found not earlier than 3
months after STZ-icv treatment. Cognitive deficits were found as early as 2 weeks
after STZ-icv treatment.
Results support STZ-icv rat as a representative experimental sAD model which
suggests that instead of Aβ, imbalance in IR signaling cascade
phosphorylation/dephosphorylation and insulin resistant brain state could be the
primary pathological event in sAD ethiopathogenesis.
Supported by Croatian MZOS (108-1080003-0020) and DAAD.