We have found that HSF1 and a proteostasis network ? the 375 chaperones, co-chaperones and proteosome subunits in the genome ? respond dramatically during feeding. Proteostasis changes in liver and skeletal muscle are the primary topics of the parent grant, but we also found proteostasis responses in cardiac muscle, kidney, adipose, jejunum and lung, so the feeding responses occur broadly across tissues. But most surprising are the feeding responses in brain, with upregulated proteostasis networks in cerebellum and hypothalamus; presumably other regions are similarly affected. These findings could be impactful, because pathophysiology in Alzheimer?s and other neurodegenerative diseases is directly linked to proteostasis. Alzheimer?s disease is characterized by the accumulation of abnormally folded proteins, e.g. extracellular A? in plaques and intracellular tau in neurofibrillary tangles, in the face of declining proteostasis capacity with age. It hasn?t been realized previously that proteostasis networks throughout the body, including brain, are dynamically regulated and highly responsive to meals and nutrients. Moreover, effect sizes for feeding are several-fold greater and more statistically robust than effect sizes in aging, suggesting inducible proteostasis may represent an untapped reservoir for translation. We therefore wish to expand on previous static, single point assessments by further characterizing these dynamic changes in brain regions relevant to Alzheimer?s disease. This supplement will provide the first data to show physiological regulation of proteostasis networks cycling daily in relevant regions of mouse brain, including cerebellum, hippocampus and cortex. We will document the effects of aging on proteostasis responses by comparing fast-fed responses in the brains of young (10-12 wk) vs. old (>90 wk) mice. Preliminary results show no change with age for fasting but seriously diminished fed responses in 22 month old mouse cerebellum. Preliminary results also show diminished fast-fed responses in liver of chow- vs HFD-fed mice, and since type 2 diabetes, insulin resistance and obesity also increase risk for Alzheimer?s, we wish to compare fast-fed responses in the same relevant regions of brain but comparing chow- vs HFD-fed mouse. Our findings are providing exciting new insights into the physiological drivers and dynamics of proteostasis, as induction by feeding occurs daily and in many tissues. Studies in brain are among the most important, as pathophysiology in Alzheimer?s disease is directly linked to the accumulation of misfolded proteins and aggregates in the face of insufficient proteostasis capacity. We hope to provide the Alzheimer?s research community with data showing that proteostasis in brain is highly dynamic as opposed to static, and readily inducible through established, potentially druggable, metabolic mechanisms and pathways. These findings are thus directly relevant to Alzheimer?s disease, and may be translated to patients.
The parent grant found that feeding and nutrients activate HSF1 and broad proteostasis responses in liver and other peripheral organs; this has not been described previously but is distinguished from heat shock-like responses through mTOR sensitivity. This supplement studies similar HSF1 activation and broad proteostasis responses in regions of brain relevant to Alzheimer?s disease, as proteostasis in these regions is thought to be linked to the pathogenesis in Alzheimer?s and related neurodegenerative diseases.
