Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model

Abstract

Latrepirdine (Dimebon™) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer’s disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine-stimulated APP catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer’s disease (AD). We utilized several mammalian cellular models to determine whether latrepirdine regulates mTOR- and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered latrepirdine prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with latrepirdine led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aβ42 and α-synuclein. We conclude that latrepirdine possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying latrepirdine effects on neurogenesis, autophagy, and behavior might warranty the further study of latrepirdine as a potentially viable lead compound that might yield more consistent clinical benefit following optimization of its pro-neurogenic, pro-autophagic, and/or pro-cognitive activities.

Aβ1-42 monomers or oligomers have different effects on autophagy and apoptosis

“…Finally, it has been found that the accumulation of insoluble Aβ1-42 and SQSTM1, a marker of autophagic flux, precedes the impairment of autophagic clearance and may be a cause of lysosomal failure. 27 Together, these data support the model in which autophagy is crucial for the removal of Aβ peptides.…”

Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis

“…Dimebon offered no protection in any of these measures. Although efficacy of Dimebon in an animal model of Alzheimer's disease (TGCRND8 mice) has recently been reported (28), this drug appears too weakly active to afford any protection in the G93A-SOD1 mutant mouse model of ALS.…”

Blocking IGF Signaling in Adult Neurons Alleviates Alzheimer's Disease Pathology through Amyloid-β Clearance

“…This supports the idea that interventions slowing down aging also postpone age-related diseases, including AD (Kenyon, 2010;Iliadi et al, 2012). In humans, disease-free survival is high in families with exceptional longevity (Sebastiani and Perls, 2012), suggesting that health span and life span are linked. Recently, pharmacological inhibition of growth hormone and IGF-I was listed as a promising strategy to retard human aging (Longo et al, 2015).…”

“…This situation is different from acute effects observed in vitro under short-term activation of autophagy, which may in turn explain why p62 levels and LC3-II/I ratios were not significantly altered in ADINKO brains, as could be expected at short term (Klionsky et al, 2012). Of note, some in vivo studies also report unchanged levels of soluble p62 upon induction of autophagy in AD brains (Steele et al, 2013) and in neurodegeneration (GhaziNoori et al, 2012). Our data are consistent with results from other model systems.…”

“…Plaques were automatically delimited and those Ն50 m 2 considered. GFAP-positive astrocytes and Iba1-positive microglial cells with DAPI-stained nucleus located within 15 m of the edge of a plaque were manually counted (Serrano-Pozo et al, 2010). Four sections were analyzed per animal to establish individual means.…”