Plasticity and vulnerability of basal forebrain cholinergic neurons in Alzheimer's Disease

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The profound loss of basal forebrain cholinergic neurons (BFCNs) is an early hallmark in Alzheimer’s disease (AD). As cholinergic innervation is essential for cognition, degeneration of BFCNs may be linked to mental decline in AD patients. Current AD therapies involving cholinergic drugs provide modest benefits but are not based on disease mechanisms and do not halt BFCN degeneration. The reasons for the vulnerability of BFCNs to cell death in AD are largely unknown, but BFCN loss predicts degeneration in cortex, and cholinesterase inhibitors reduce atrophy in basal forebrain as well as cortex and hippocampus. These observations support the premise that protection of BFCNs could slow pathogenesis in AD. Thus, there is an urgent need to identify molecular mechanisms of cell death in BFCNs. In this proposal, we will investigate molecular events associated with BFCN dysfunction. We focus on neuronal hyperexcitability, which is a prominent, early feature in AD patients linked to cognitive deficits. Hyperactivity induces homeostatic synaptic plasticity (HSP), a compensatory mechanism that tunes synaptic strength in response to perturbations in neuronal activity, thereby maintaining excitation within an optimal range and preserving network stability. However, little is known regarding HSP in mammalian CNS cholinergic synapses, in normal conditions or in AD models. We will test the hypothesis that hyperexcitation and HSP mechanisms exacerbate AD pathogenesis. Furthermore, we propose that BFCNs, which are highly vulnerable and affected early in AD, provide a sensitive readout for detecting such dysfunctions. We propose the following aims: 1) Using an optimized septal-hippocampal co-culture system, we will examine the course of normal BFCN and cholinergic synapse development; determine morphological and functional changes that occur in cholinergic neurons and synapses during overexcitation conditions; and utilize similar co-cultures prepared from an AD mouse model to examine the perturbations to BFCNs in their normal development, response to hyperexcitation, and susceptibility to distinct forms of cell death. 2) We will analyze BFCNs and target hippocampal neurons in vivo with multidisciplinary approaches to examine the homeostatic responses to hyperexcitation, and use ChAT-Cre mice crossed to an AD mouse model to identify impairments in BFCN structure or synaptic function, under both basal and hyperexcitation conditions. These significant studies use innovative technology to investigate questions of basic and translational importance. If successful, the findings may lead to improved therapies against BFCN neurodegeneration in AD.