The growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling pathway has been strongly implicated in the modulation of the aging process. However, studies examining the relationship involving IGF-1, the brain and neurodegenerative diseases, such as Alzheimer's Disease (AD), have proven far more complex. Central administration of IGF-1 can produce favorable effects on features of normal brain aging. However, early optimism that raising peripheral IGF-1 could treat AD was dampened when these findings could not be replicated, while models of reduced IGF-1 signaling actually slowed progression of symptoms in mouse models of human cerebral A? amyloidosis. As opposed to peripheral dosing, we have found that intranasal (IN) treatment with IGF-1 to target the brain can improve many facets of cognitive aging in mice. However, a paucity of data exists examining the therapeutic potential of IN IGF-1 in aging, dementia or cerebral amyloidosis. Recent disappointing reports from an IN insulin trial (?SNIFF?) shift attention toward ligands other than insulin as candidates for IN delivery. While it is generally accepted that cognitive decline in AD usually appears after some longstanding A? amyloidosis and temporally coincides with the appearance of tauopathy, neuroinflammation, and neurodegeneration, the etiology of cognitive decline in type 2 diabetes (T2D) may instead be attributed to vascular dysfunction. To this end, it is worth noting that IGF-1 has not only been shown to promote A? uptake and protect neurons and synapses, but also opposes rarefaction of the vasculature. Therefore, this proposal aims to directly address the impact of these two critical metabolic hormones to cognitive decline and AD. We hypothesize that IGF-1 is uniquely positioned to modulate or prevent initiation of some features important to the pathogenesis of: (1) normal brain aging, (2) age-related cognitive impairment due to A? amyloidosis, (3) VCID, and/or (4) the evolution from presymptomatic to symptomatic phase. We further propose that this ?window of opportunity? may close as pathology progresses. We will test this possibility in Aim 1 by evaluating the ability of IN insulin versus IGF-1 to delay cognitive decline and related underlying changes in brain aging, using a combination of functional, molecular, and BOLD-fMRI imaging approaches.
In Aim 2 we will further explore the possibility that a critical `therapeutic window' for IN insulin or IGF-1 treatment may exist in a mouse model of A? amyloidosis, whereby beneficial effects early in disease may?when sustained later into illness?transition in valence toward ineffective or deleterious. Finally, Aim 3 will evaluate the ability of IN insulin versus IGF-1 to delay cognitive decline and associated pathologic changes in a mouse model of vascular and mixed dementia. These studies should better define the central actions of insulin versus IGF-1 and their ability to prevent or delay cognitive decline in aging, vascular and mixed dementia, and/or the evolution of symptomatic AD. Furthermore, these studies should establish the potential therapeutic window for these effects, and ultimately help to reconcile contradictory evidence regarding the role of IGF-1 across the evolution of cognitive impairment and AD.
This proposal is aimed to perform a side-by-side comparison of intranasal insulin versus IGF-1 treatment as a means of targeting the brain on cognitive decline in aging, vascular disease, and A? amyloidosis. We anticipate that intranasal IGF-1 is uniquely positioned to modulate or prevent initiation of some features important to the pathogenesis of cognitive decline as well as the evolution from presymptomatic to symptomatic phase of Alzheimer's disease. Ultimately, these studies should better inform as to the relative efficacy of IGF-1, the probable `therapeutic window', and those patients most likely to benefit from treatment.
