Bonnie Cooper

The interaction of amyloid-beta (Aβ) and tau in the pathogenesis of Alzheimer's disease is a subject of intense inquiry, with the bulk of evidence indicating that changes in tau are downstream of Aβ. It has been shown however, that human tau overexpression in amyloid precursor protein transgenic mice increases Aβ plaque deposition. Here, we confirm that human tau increases Aβ levels. To determine if the observed changes in Aβ levels were because of intracellular or extracellular secreted tau (eTau for extracellular tau), we affinity purified secreted tau from Alzheimer's disease patient-derived cortical neuron conditioned media and analyzed it by liquid chromatography-mass spectrometry. We found the extracellular species to be composed predominantly of a series of N-terminal fragments of tau, with no evidence of C-terminal tau fragments. We characterized a subset of high affinity tau antibodies, each capable of engaging and neutralizing eTau. We found that neutralizing eTau reduces Aβ levels in vitro in primary human cortical neurons where exogenously adding eTau increases Aβ levels. In vivo, neutralizing human tau in 2 human tau transgenic models also reduced Aβ levels. We show that the human tau insert sequence is sufficient to cause the observed increase in Aβ levels. Our data furthermore suggest that neuronal hyperactivity may be the mechanism by which this regulation occurs. We show that neuronal hyperactivity regulates both eTau secretion and Aβ production. Electrophysiological analysis shows for the first time that secreted eTau causes neuronal hyperactivity. Its induction of hyperactivity may be the mechanism by which eTau regulates Aβ production. Together with previous findings, these data posit a novel connection between tau and Aβ, suggesting a dynamic mechanism of positive feed forward regulation. Aβ drives the disease pathway through tau, with eTau further increasing Aβ levels, perpetuating a destructive cycle.

A spontaneous motor neuron disease or neuronopathy was identified in 10 horses from the northeastern United States. Signs of generalized weakness, muscle fasciculations, muscle atrophy and weight loss progressed over 1 to several months in young and old horses of various breeds. Pathologic studies revealed that degeneration and loss of motor neurons in the spinal cord and brain stem resulted in axonal degeneration in the ventral roots and peripheral and cranial nerves and denervation atrophy of skeletal muscle. Many spinal neurons were swollen, chromatolytic and contained neurofilamentous accumulations. Other cell bodies were shrunken and undergoing neuronophagia and some were lost and replaced by glia. This fatal equine motor neuron disease has not been reported previously and its cause has not been determined. The progressive weakness and wasting and the neuronal degenerative changes in these horses were similar to those described in people with sporadic amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

The superior colliculus (SC) has long been associated with the neural control of eye movements. Over seventy years ago, the orderly topography of saccade vectors and corresponding visual field locations were discovered in the cat SC. Since then, numerous high-impact studies have investigated and manipulated the relationship between visuotopic space and saccade vector across this topography to better understand the physiological underpinnings of the sensorimotor signal transformation. However, less attention has been paid to the other motor responses that may be associated with SC activity, ranging in complexity from concerted movements of skeletomotor muscle groups, such as arm-reaching movements, to behaviors that involve whole-body movement sequences, such as fight-or-flight responses in murine models. This review surveys these more complex movements associated with SC (optic tectum in nonmammalian species) activity and, where possible, provides phylogenetic and ethological perspective.