When the proteins begin to dismantle connections within the brain cells, however, the rapid severity of memory loss is typically associated with Alzheimer’s disease (AD).

A scientific group led by TGen recently identified three kinases, or proteins, that may offer insights into how memory functions and how scientists differentiate naturally occurring memory loss from Alzheimer’s disease.

The findings, resulting from a multi-year TGen study, appeared in the January edition of BMC Genomics.

The study identified three kinases that trigger a malfunction in tau, a protein critical to the formation of the microtubule bridges within brain cells, or neurons. These bridges support the synaptic connections that, like computer circuits, allow the brain’s neurons to communicate with each other.

“The ultimate result of tau dysfunction is that neurons lose their connections to other neurons, and when neurons are no longer communicating, that has profound effects on cognition — the ability to think and reason,’’ said Dr. Travis Dunckley, an Associate Investigator in TGen’s Neurodegenerative Research Unit and the paper’s senior author.

Tau performs a critical role in the brain by helping bind together microtubules, which are sub-cellular structures that create scaffolding in the neurons, allowing them to stretch out along bridges called axons. The axons support the synaptic, or chemical, connections with other neurons.

Under normal circumstances, kinases regulate tau by adding phosphates. This process, called tau phosphorylation, enables the microtubules to unbind and then bind again, allowing brain cells to connect and reconnect with other brain cells.

“That facilitates synaptic plasticity. It facilitates the ability of people to form new memories — to form new connections between different neurons — and maintain those memories. So, it’s an essential function,’’ Dr. Dunckley said.

However, sometimes the tau protein becomes hyperphosphorylated, a condition in which the tau creates neurofibrillary tangles, one of the signature indicators of Alzheimer’s.

“When tau protein is hyperphosphorylated, the microtubule comes apart - basically destroying that bridge - and the neurons can no longer communicate with each other,’’ Dr. Dunckley said.

Investigators identified 26 proteins associated with the phosphorylation of tau, and found that three caused hyperphosphorylation of tau, permanently dismantling the microtubule bridges.

“This paper shows, for the first time, these three kinases affect Alzheimer’s disease-relevant tau hyperphosphorylation, in which most of the tau protein is now driven into a permanently phosphorylated (or inactive) form,’’ Dr. Dunckley said.

The next step will be to identify drug compounds that can negate the effects of the three kinases linked to tau hyperphosphorylation.

TGen’s collaborators in the study included: the Department of Neurology at the Mayo Clinic in Jacksonville, Fla.; the Center for Alzheimer’s Research at the Sun Health Institute in Sun City, Ariz.; Banner Alzheimer’s Institute in Phoenix, Ariz.; the Department of Psychiatry at the University of Arizona; and the Arizona Alzheimer’s Consortium, a group of nine institutes that cooperatively study Alzheimer’s disease.