Fellow's research: Mechanism for modified brain activity in Alzheimer's Disease
20 May 2020
Suhita Nadkarni, Intermediate fellow, IISER Pune
Our recently published study shows modified brain activity patterns in Alzheimer’s disease are caused by a lowered presence of ion channels called the HCN. The lower presence of these HCN channels lowers the power of a specific brain activity pattern. It also makes this pattern unreliable and triggers plaque formation.
Alzheimer’s Disease is a catastrophic disease that initially affects memory and cognition. It is also a messy disease since it involves multiple brain areas and cellular changes, making it difficult to arrive at cause-effect relationships. Some of the characteristic changes include aggregation of amyloid-beta plaques, modified expression of ion channels, and alterations in calcium signaling.
Robust brain activity patterns that represent important functions are also seen to be modified initially in AD. We investigated the alpha rhythm, associated with attention and learning. We asked what are the underlying neural mechanisms that lead to the pathological changes in the rhythm?
We use a realistic computational model of the thalamus to tease-out the causal links between molecular changes in Alzheimer’s disease and their effect on the alpha rhythm. Our model demonstrates that the lower expression of HCN (hyperpolarization-activated cyclic nucleotide-gated channels) crucial for alpha generation, alters calcium signaling, modifies excitation-inhibition balance in the thalamus makes the network more sensitive to noise.
Amongst the myriad of molecular changes associated with Alzheimer’s disease, our investigation focusses on three critical changes observed as early pathologies. Each of these are either independent observations or seen as a correlated change with the other, leading to a few dozen possibilities of causal relationships.
Causality between Amyloid beta plaques (top left), HCN Channel expression (top right) and the Alpha rhythm (bottom).
Our model, when seen in conjunction with diverse experimental data, narrows it down to a small subgroup of possibilities shown in the illustration. It establishes a causal relationship between the downregulation of HCN channels and modification in the occipital alpha rhythm. Lower expression of HCN channels is also seen to cause amyloid beta plaques. Present understanding does not allow us to confirm the causal relationship between plaques and alpha rhythm.
Our findings advance the understanding of novel drug targets for AD. Currently used drugs increase the acetylcholine levels in brain show temporary relief of symptoms. These drugs also rescue the modified alpha rhythm. However, this rescue is possible only over a limited range of reduced HCN expression. Our results strongly suggest HCN as a potent therapeutic target rather than modified cholinergic signaling.
Biophysical basis of alpha rhythm disruption in Alzheimer’s disease. Rohan Sharma, Suhita Nadkarni. Eneuro 7, no. 2 (2020).