Alzheimer's disease

CENTRAL NERVOUS SYSTEM

Porsolt offers models in all areas of psychopharmacology, epilepsy, sleep-wake, and neurodegenerative disorders. We are uniquely placed to offer a full range of CNS efficacy and safety pharmacology assessments, from basic models and regulatory tests, through the evaluation of abuse and dependence liability and proconvulsant risk using EEG.

Alzheimer's disease

Alzheimer’s disease (AD) is one of the major neurodegenerative diseases affecting millions of people worldwide and lacking effective therapeutic intervention. AD is characterized by memory deficits and rarely by movement impairment.

The development of new therapeutic strategies remains a priority for limiting the progression of these diseases and the treatment of symptoms. Porsolt develops models and tests  for assessing potential new therapies.

Alzheimer’s disease & Tauopathy | in vitro models

Hyper-phosphorylation of Tau and aberrant gamma-secretase activity are respectively involved in the formation of intracellular neurofibrillary tangles and in the extracellular deposition of amyloid plaques in the brain – the two hallmarks of Alzheimers’s disease.

Two in vitro pharmacological cell models are available at Porsolt to identify or characterize compounds targeting Tau phosphorylation cascade or γ-secretase activity:

➤ GAMMA-SECRETASE ACTIVITY WITH RECOMBINANT BIOSENSOR IN HETEROLOGOUS CELL CLONE

Porsolt developed a proprietary biosensor based on a GFP-like reporter linked to C99 protein (beta-amyloid precursor), which is specifically cleaved by gamma-secretase.

The resulting assay, optimized for high-throughput screening, is particularly suited for the selection of gamma-secretase inhibitors:

> Cost-efficientreagentless quantification of γ-secretase activity by flow cytometry

> High-throughput: stably expressed in human cell clones cultured in microplate format

> Robust: our gamma-secretase assay was cross-validated by immunocytochemistry.

 

See below the principle of Porsolt's gamma-secretase activity assay based on DAPs technology ↴

➤ OKADAIC ACID-INDUCED TAU HYPER-PHOSPHORYLATION ASSAY

Porsolt developed an in vitro cellular model of tauopathy to identify and characterize compounds preventing Tau hyper-phosphorylation:


> A well-characterized and predictive pharmacological model of Tauopathy: primary rat cortical cultures are treated with okadaic acid in microplates.

> A straightforward readout: phospho-Tau is quantified at the single-cell level using immunofluorescence & high-content imaging.

Alzheimer’s disease | in vivo models

➤ STREPTOZOTOCIN (STZ) - INDUCED COGNITIVE DEFICIT.

Although the cause of AD remains unknown, the sporadic form is mainly related to aging and other risk factors such as diabetes and metabolic disturbances.

Intracerebroventricular administration of STZ induces biochemical changes in the brain contributing to the appearance of memory impairments in the rat.

> Suggested approach: Evaluation of motor coordination by Morris water maze and delayed-alternation test

MORRIS WATER MAZE

Assessment of learning and spatial memory as indicated by a decrease in the escape latency (time spent to reach the hidden platform ) from one day to the next.

DELAYED-ALTERNATION TEST

Assessment of working memory, attention, and decision making: the animal has to learn to press the opposite lever to that previously presented (correct responses) to gain a food reward (nonmatching to sample).