A role for calcineurin in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is an incurable age-related neurodegenerative disorder characterized by profound memory dysfunction. This bellwether symptom suggests involvement of the hippocampus -- a brain region responsible for memory formation -- and coincidentally an area heavily burdened by hyperphosphorylated tau and neuritic plaques of amyloid beta (Aβ). Recent evidence suggests that pre-fibrillar soluble Aβ underlies an early, progressive loss of synapses that is a hallmark of AD. One of the downstream effects of soluble Aβ aggregates is the activation of the phosphatase calcineurin (CaN). This review details the evidence of CaN hyperactivity in 'normal' aging, models of AD, and actual disease pathogenesis; elaborates on how this could manifest as memory impairment, neuroinflammation, hyperphosphorylated tau, and neuronal death.

Keywords: Alzheimers; amyloid beta; calcineurin; calcium..

Fig. (1)

Calcineurin in the aging AD brain. The aged brain is susceptible to hyperactivation of CaN and downstream consequences due to its decreased ability to regulate intracellular Ca²⁺ levels. The additional insult of Aβ oligomers further disrupts synaptic homeostasis, resulting in a subtle, prolonged increase in calcium that facilitates the expression of LTD. Activation of CaN by CaM disrupts the phosphatases interaction with tau, possibily leading to tau hyperphosphorylation [92]. CaN also mediates the dephosphorylation of several cellular proteins: pCREB [8], pNFAT [81], p-PP1 [13, 53], p-GSK-3 [16], and pBAD [10, 11]. This could putatively explain four observations in AD models and pathogenesis; synaptic protein loss, neuroinflammation (neuronal and astrocytic), decreased neurotransmission, hyperphosphorylated tau, and cell death. Therefore, inhibition of CaN or the promotion of positive plasticity may serve as viable therapeutic strategies for combating early stage AD impairment.