A Small Compound Targeting Prohibitin with Potential Interest for Cognitive Deficit Rescue in Aging mice and Tau Pathology Treatment

Abstract

Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We analyzed the effects of a new purine derivative drug, PDD005, in attenuating mechanisms involved in the pathogenesis of neurodegenerative diseases, using both in vivo and in vitro models. We show that PDD005 is distributed to the brain and can rescue cognitive deficits associated with aging in mice. Treatment with PDD005 prevents impairment of neurogenesis by increasing sex-determining region Y-box 2, nestin, and also enhances synaptic function through upregulation of synaptophysin and postsynaptic density protein 95. PDD005 treatment also reduced neuro-inflammation by decreasing interleukin-1β expression, activation of astrocytes, and microglia. We identified prohibitin as a potential target in mediating the therapeutic effects of PDD005 for the treatment of cognitive deficit in aging mice. Additionally, in the current study, glycogen synthase kinase appears to attenuate tau pathology. Based on current statistics, disorders of the central nervous system (CNS) will become a significant healthcare issue in the 21st century. Neurodegenerative disorders (NDs) can have a substantial impact on the quality of life for patients, often associated with progressive debilitation. Alzheimer's disease and Parkinson's disease are the most common forms of NDs for which the principal risk factor is age 1. Current therapeutic strategies often treat only the symptoms of the disease and can have problematic side effects in some patients. NDs are characterized by aggregation and accumulation of cellular proteins 2. For instance, in Alzheimer's disease, cellular metabolism dysfunction in the CNS results in the accumulation of amyloid β (Aβ) peptides (Aβ-42 and Aβ-40) and hyperphosphorylation of tau protein, which are associated with selective loss of neurons in the brain 3. Abnormal protein aggregation in the brain is also associated with inflammation 4 and impaired neurogenesis 5. A recent study

SFPH proteins as therapeutic targets for a myriad of diseases

“…The adenine derivative PDD005 is a PHB ligand that rescues cognitive deficits associated with aging in mice. 42 It also alleviates neurogenesis deficiency and inhibits neuro-inflammation, confirming PHBs as emerging therapeutic targets against neurodegenerative diseases.…”

Activation of the Integrated Stress Response and ER Stress Protect from Fluorizoline-Induced Apoptosis in HEK293T and U2OS Cell Lines

“…Furthermore, PHBs are important in the regulation of cristae morphology, reactive oxygen species formation, or mitophagy [ 4 , 5 , 11 ]. Different molecules have been described to interact with PHBs [ 12 , 13 , 14 ]. We previously demonstrated that PHBs are required for the proapoptotic effect of fluorizoline in mouse embryonic fibroblasts as well as in HEK293T and U2OS human cell lines [ 15 , 16 ].…”

Prohibitin ligands: a growing armamentarium to tackle cancers, osteoporosis, inflammatory, cardiac and neurological diseases

“…Thereafter, an analogue, PDD005 (28), was found to display opposite effects [96]. Indeed it rescues cognitive deficits associated with aging in mice.…”