Abstract
Alzheimer’s disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive deficits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure. Here, we tested the efficacy of a novel synaptogenic small molecule, SPG302 — a 3rd-generation benzothiazole derivative that increases the density of axospinous glutamatergic synapses — in 3xTg-AD mice. Daily dosing of 3xTg-AD mice with SPG302 at 3 and 30 mg/kg (i.p.) for 4 weeks restored hippocampal synaptic density and improved cognitive function in hippocampal-dependent tasks. Mushroom and stubby spine profiles were increased by SPG302, and associated with enhanced expression of key postsynaptic proteins — including postsynaptic density protein 95 (PSD95), drebrin, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) — and increased colocalization of PSD95 with synaptophysin. Notably, SPG302 proved efficacious in this model without modifying Aβ and tau pathology. Thus, our study provides preclinical support for the idea that compounds capable of restoring synaptic density offer a viable strategy to reverse cognitive decline in AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia world-wide, estimated to afflict 50 million people by 2050
To evaluate the cognitive effects of SPG302, wild type (WT) and 3xTg-AD mice at 6 months of age were dosed daily for 4 weeks with either vehicle or SPG302 at 3 or 30 mg/kg (i.p.), with behavioral assessments conducted during the 4th week, followed by sacrifice for performance of histological and biochemical assays in brains from the same animals
To assess whether SPG302 rescues cognitive function in 3xTg-AD mice, we evaluated spatial memory in vehicle and SPG302-treated WT and 3xTg-AD mice using the Morris water maze (MWM) test (Fig. 1A). 3xTg-AD mice treated with vehicle showed severe impairments in learning during acquisition of the spatial task compared to vehicle-treated WT mice
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia world-wide, estimated to afflict 50 million people by 2050. LaFerla contributed to this work the estimated total expenses for AD in 2020 is $305 billion, with the cost expected to increase to more than $1 trillion by 2050 [1]. Greater than century long recognition as a clinical entity, disease-modifying therapies remain elusive [2]. In the last 20 years, over 150 clinical stage drugs have failed, dominated recently by a string of failures among therapies targeting amyloid beta (Aβ), and
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