geranylgeranylacetone and Alzheimer-Disease

Teprenone (geranylgeranylacetone), an anti-ulcer agent, has been reported to inhibit amyloid-β increase, senile plaque formation, and neuronal degeneration, and improve memory in mouse models of Alzheimer's disease (AD).. We conducted a randomized, double-blind, placebo-controlled study to ascertain teprenone's therapeutic ability for AD.. Patients with mild to moderate AD, with a Mini-Mental State Examination (MMSE) score of 13 to 26, were randomly allocated into two groups depending on the administered drug: donepezil +  placebo (placebo group) and donepezil + teprenone (teprenone group). The primary and secondary endpoints included changes in scores of the Japanese version of the AD Assessment Scale-cognitive subscale (ADAS-J cog) and other evaluations, respectively, including MMSE scores, during a 12-month period after the first administration.. Forty-two and thirty-seven patients were allocated to the teprenone and placebo groups, respectively. ADAS-J cog score changes were not different between groups (placebo, 0.6±0.8; teprenone, 0.4±0.8; p = 0.861). However, MMSE scores significantly improved in the teprenone group (placebo, - 1.2±0.5; teprenone, 0.2±0.5; p = 0.044). Subgroup analysis considering the severity of medial temporal area atrophy revealed that this improvement by teprenone was significant in patients with mild (p = 0.013) but not with severe atrophy (p = 0.611). Adverse events were observed in 17.8 and 10.4% of patients in the placebo and teprenone group, respectively.. Teprenone may be effective for AD when administered before atrophy progression in the medial temporal areas.. UMIN ID: UMIN000016843.

Topics: Aged; Alzheimer Disease; Anti-Ulcer Agents; Atrophy; Cognition; Diterpenes; Donepezil; Double-Blind Method; Drug Monitoring; Drug Repositioning; Female; Humans; Male; Mental Status and Dementia Tests; Nootropic Agents; Severity of Illness Index; Temporal Lobe; Treatment Outcome

Amyloid-β peptide (Aβ) plays an important role in the pathogenesis of Alzheimer's disease (AD). Aβ is generated by the secretase-mediated proteolysis of β-amyloid precursor protein (APP), and cleared by enzyme-mediated degradation and phagocytosis. Transforming growth factor (TGF)-β1 stimulates this phagocytosis. We recently reported that the APP23 mouse model for AD showed fewer AD-related phenotypes when these animals were crossed with transgenic mice expressing heat shock protein (HSP) 70. We here examined the effect of geranylgeranylacetone, an inducer of HSP70 expression, on the AD-related phenotypes. Repeated oral administration of geranylgeranylacetone to APP23 mice for 9 months not only improved cognitive function but also decreased levels of Aβ, Aβ plaque deposition and synaptic loss. The treatment also up-regulated the expression of an Aβ-degrading enzyme and TGF-β1 but did not affect the maturation of APP and secretase activities. These outcomes were similar to those observed in APP23 mice genetically modified to overexpress HSP70. Although the repeated oral administration of geranylgeranylacetone did not increase the level of HSP70 in the brain, a single oral administration of geranylgeranylacetone significantly increased the level of HSP70 when Aβ was concomitantly injected directly into the hippocampus. Since geranylgeranylacetone has already been approved for use as an anti-ulcer drug and its safety in humans has been confirmed, we propose that this drug be considered as a candidate drug for the prevention of AD.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Brain; Cognition; Disease Models, Animal; Diterpenes; Enzyme Activation; Female; Gene Expression; HSP70 Heat-Shock Proteins; Maze Learning; Mice; Neuroeffector Junction; Phenotype