A potential connection between the accumulation of amyloid-beta (Aβ) and disturbances in neural network activity—two key pathological features of Alzheimer's disease (AD)—was recently identified in a study published in Acta Neuropathologica Communications.
Researchers found presenilin 1 (PS1), a component of the enzyme γ-secretase involved in Aβ production, also interacts with GLT-1 (EAAT2 in humans), the primary glutamate transporter in the brain. This interaction appears to be altered in AD, possibly contributing to progression of the disease.
Alzheimer's disease is characterized by the presence of amyloid plaques and neurofibrillary tangles, alongside cognitive decline. Glutamate, the brain's main excitatory neurotransmitter, is tightly regulated by transporters like GLT-1 to prevent overexcitement of neurons, which can cause damage. Recent findings suggest PS1 acts as a "chaperone" for GLT-1, aiding in its surface expression and multimerization, which are crucial for proper glutamate transport.
The study demonstrated that sporadic Alzheimer’s disease (sAD) brains showed a reduced interaction between PS1 and GLT-1 compared to both control brains and those affected by frontotemporal lobar degeneration (FTLD), another form of dementia without amyloid pathology. The researchers noted that the disruption of the PS1 and GLT-1 interaction may be specific to AD.
In both sporadic and familial forms of AD, mutations in PS1 can lead to a "closed" pathogenic conformation of the protein, which impairs its ability to bind to GLT-1. This conformational change in PS1 may diminish its role as a chaperone for GLT-1, contributing to the impaired regulation of glutamate levels in the brain. By contrast, using gamma-secretase modulators (GSMs) to induce a "relaxed" PS1 conformation increased the interaction between PS1 and GLT-1. The researchers suggested this as a novel potential therapeutic avenue.
The study found that in Alzheimer's brains, GLT-1 exhibited higher levels of aggregation and decreased solubility. Functional forms of GLT-1, typically seen as trimers, were replaced by less mature dimers in affected tissues. This disruption in GLT-1 maturation and surface expression might impair its ability to clear glutamate from synapses, potentially leading to the hyperactive neural circuits observed early in Alzheimer’s progression, the researchers wrote.
Further investigation is needed to fully elucidate the regulatory mechanisms of this interaction and its effects on glutamate homeostasis in vivo, the noted. By exploring how PS1’s altered conformation affects glutamate transporter functionality, future studies might identify targeted treatments that could help maintain normal brain activity and mitigate some of the neurodegenerative processes associated with AD.
