Abstract
The development of an effective therapy for Alzheimer’s disease (AD) is a major challenge to biomedical sciences. Because much of early AD pathophysiology includes hippocampal abnormalities, a viable treatment strategy might be to use trophic factors that support hippocampal integrity and function. IGF2 is an attractive candidate as it acts in the hippocampus to enhance memory consolidation, stimulate adult neurogenesis and upregulate cholinergic marker expression and acetylcholine (ACh) release. We performed a seven-day intracerebroventricular infusion of IGF2 in transgenic APPswe.PS1dE9 AD model mice that express green fluorescent protein in cholinergic neurons (APP.PS1/CHGFP) and in wild type WT/CHGFP littermates at 6 months of age representing early AD-like disease. IGF2 reduced the number of hippocampal Aβ40- and Aβ42-positive amyloid plaques in APP.PS1/CHGFP mice. Moreover, IGF2 increased hippocampal protein levels of the ACh-synthesizing enzyme, choline acetyltransferase in both WT/CHGFP and APP.PS1/CHGFP mice. The latter effect was likely mediated by increased protein expression of the cholinergic differentiating factor, BMP9, observed in IGF2-treated mice as compared to controls. IGF2 also increased the protein levels of hippocampal NGF, BDNF, NT3 and IGF1 and of doublecortin, a marker of neurogenesis. These data show that IGF2 administration is effective in reversing and preventing several pathophysiologic processes associated with AD and suggest that IGF2 may constitute a therapeutic target for AD.
Highlights
Alzheimer’s disease (AD) pathology is characterized by cerebral accumulation of extracellular amyloid, intraneuronal neurofibrillary tangles, neurotransmitter abnormalities and, loss of synapses and neuronal death
Reduction of Ab accumulation and generation of a trophic environment for basal forebrain cholinergic neurons (BFCN) are rational objectives in designing an AD therapy. We tested this idea using insulin-like growth factor 2 (IGF2) as a therapeutic agent based on studies showing that IGF2 mRNA levels decline in the frontal cortex of AD patients at relatively early stages of neuropathology (Braak and Braak 2–3) [9] and on a growing body of data showing beneficial effects of IGF2 on neural function
The results show that administration of IGF2 to the brain of the AD model APP.PS1/CHGFP mice ameliorates the central pathophysiologic feature of AD, the accumulation of amyloid plaques in the hippocampus
Summary
Alzheimer’s disease (AD) pathology is characterized by cerebral accumulation of extracellular amyloid, intraneuronal neurofibrillary tangles, neurotransmitter abnormalities and, loss of synapses and neuronal death. Reduction of Ab accumulation and generation of a trophic environment for BFCN are rational objectives in designing an AD therapy. We tested this idea using insulin-like growth factor 2 (IGF2) as a therapeutic agent based on studies showing that IGF2 mRNA levels decline in the frontal cortex of AD patients at relatively early stages of neuropathology (Braak and Braak 2–3) [9] and on a growing body of data showing beneficial effects of IGF2 on neural function. IGF2 is expressed in the subgranular zone of the dentate gyrus, and endogenous IGF2 upregulates the proliferation of neural stem cells in this brain region [15] and, intrahippocampal injections of IGF2 promote the survival of adult-born neurons in the dentate granule cell layer [12,13]. IGF2 increases the release of acetylcholine (ACh) from BFCN [16,17,18] and prevents the Ab-evoked neurotoxicity in cultured septal neurons [19] and in hippocampal cultures [20]
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