Tracking the history of where research in Alzheimer’s disease (AD) has been difficult leads you naturally to the ‘amyloid story’. Many people now believe that an alteration in brain levels of amyloid ?-proteins (A?) plays a major pathogenic role in AD, a devastating neurodegenerative disorder that causes progressive cognitive impairment and memory loss. AD is characterized by abnormal accumulation of A? in the brain, which leads to the formation of protein aggregates that are toxic to neurons. A? peptides are generated when a large protein called amyloid precursor protein (APP) is cut up into smaller pieces. However, it remains a reasonably consistent observation that the earliest symptoms in AD are early memory deficits. Why, if the build-up of amyloid is widespread, is it the memory that is most remarkable?

Recently, there was a fascinating paper from new research which helped to shed light on the events that underlie the “spread” of AD throughout the brain. The research, published by Neuron [Cell Press] in a recent issue of the journal Neuron, follows disease progression from a vulnerable brain region that is affected early in the disease to interconnected brain regions that are affected in later stages. Important for society in the future is that these findings may contribute to design of therapeutic interventions as targeting the brain region where AD originates would be simpler than targeting multiple brain areas.

The entorhinal cortex (EC) is one of the earliest affected, most vulnerable brain regions in Alzheimer’s disease (AD), which is associated with amyloid-? (A?) accumulation in many brain areas. Communication between the EC and the hippocampus is critical for memory and disruption of this circuit may play a role in memory impairment in the beginning stages of AD. Neuroscientists in recent years have felt that it is the entorhinal cortex (and the perirhinal cortex of the parahippocampal cortex) that may contribute to the memory deficits of humans more than possibly the hippocampus itself.

It had not been not clear how EC dysfunction contributes to cognitive decline in AD or whether early vulnerability of the EC initiates the spread of dysfunction through interconnected neural networks. The authors of this study produced transgenic mice with spatially restricted overexpression of mutant APP primarily in neurons of the EC. Selective overexpression of mutant amyloid precursor protein (APP) predominantly in layer II/III neurons of the EC caused cognitive and behavioral abnormalities characteristic of mouse models with widespread neuronal APP over-expression, including hyperactivity, disinhibition, and spatial learning and memory deficits. Importantly, these abnormalities are similar to those observed in mouse models of AD with mutant APP expression throughout the brain.

The researchers also observed abnormalities in the hippocampus, including dysfunction of synapses and A? deposits in part of the hippocampus that receive input from the EC.
The authors concluded that this directly supports the hypothesis that AD-related dysfunction is propagated through networks of neurons, with the EC as an important hub region of early vulnerability.

This work is still entirely consistent with the exciting prospect of immunizing against amyloid in human brains one day in early Alzheimer’s disease (and the mouse models), improving function. Watch this space!

References

H. Braak and E. Braak. Neuropathological stageing of Alzheimer-related changes. [Review.] Acta neuropathol
Volume 82, Number 4 [1991] 239-259, DOI: 10.1007/BF00308809

Julie A. Harris, Nino Devidze, Laure Verret, Kaitlyn Ho, Brian Halabisky, Myo T. Thwin, Daniel Kim, Patricia Hamto, Iris Lo, Gui-Qiu Yu, Jorge J. Palop, Eliezer Masliah, Lennart Mucke. Transsynaptic Progression of Amyloid-?-Induced Neuronal Dysfunction within the Entorhinal-Hippocampal Network. Neuron, 2010; 68 (3): 428-441