Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) in transgenic mouse models of frontotemporal lobar degeneration and Alzheimer’s disease

Abstract

Alzheimer’s disease (AD), the most common dementia, is characterized by potentially neurotoxic aggregation of Aβ peptide and tau protein, and their deposition as amyloid plaques and neurofibrillary tangles (NFTs). Tau aggregation also occurs in other common neurodegenerative diseases. Frontotemporal dementia (FTD) can be caused by tau mutations that increase the susceptibility of tau to hyperphosphorylation and aggregation, which may cause neuronal dysfunction and deposition of NFTs. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a potent inhibitor of heat shock protein 90 (Hsp90), a cytosolic chaperone implicated in the proper folding and functions of a repertoire of client proteins. 17-AAG binds to Hsp90 and enhances degradation of Hsp90 client protein. We sought to determine whether 17-AAG can reduce Aβ and tau pathology in the brains of AD and FTD model mice expressing Aβ or P301L mutant tau, respectively. Mice were randomized to receive 25, 5, or 0 mg/kg 17-AAG thrice weekly from age eight to 11 months. Analysis was performed by rotarod test on motor function, on the area occupied by plaques in hippocampus or NFTs in medulla tissue sections, and on mortality. A high dose of 17-AAG tended to decrease NFTs in male mice (p = 0.08). Further studies are required to confirm the effect of 17-AAG in diseases of tau aggregation.

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

“…17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a potent inhibitor of Hsp90. A high dose of 17-AAG decreased neurofibrillary tangles in male P301L mutant mice [29]. It attenuated A␤induced synaptic toxicity and memory impairment [30].…”

The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained

“…Treatment with Arimoclomol, a co-inducer of the heat shock response, delayed disease progression and extended the lifespan of SODG93A mice, and is currently being investigated in phase II/III clinical trial for ALS patients with SOD1 mutations (83). Celastrol and Tanespimycin, which target the heat shock protein response, are other potential drugs that have shown promise in transgenic mouse model of Alzheimer’s disease as well as ALS (84–86) (Table 1). Thus, multiple studies reviewed above are promising and suggest that targeting the cellular protein quality control system of the ER is an attractive strategy for the treatment of neurodegenerative conditions.…”

Targeting Hsp90 and its co-chaperones to treat Alzheimer’s disease

“…Improving upon the potency and safety of GA led to the second generation of Hsp90 inhibitors, including the well-known, less toxic analog 17-(allylamino)-17-demethoxygeldamycin (17-AAG). This class of inhibitors binds to the N-terminus of Hsp90 and was shown to preferentially bind to Hsp90 in a disease state 52 and effectively clear tau in a mouse model of tauopathies 25 . This scaffold, while promising, has multiple off-target effects including eliciting a strong heat shock response 24 .…”

“…A direct link between chaperone regulation and Aβ was demonstrated when a heat shock element, controlled by heat shock factor 1 (HSF1), was identified in the promoter of the APP gene 22 . Hsp90 inhibitors are protective against Aβ-induced toxicity 23 , rescuing Aβ-induced cognitive impairment in mice 24 , while leaving Aβ plaque load unchanged 25 . However, more studies need to be done to parse out the direct effects of Hsp90 inhibition on Aβ, independent of the elevation of Hsp70 and Hsp27 which occurs with most Hsp90 inhibitors.…”