A bidirectional deep brain interface to unravel the pathogenic role of vascular amyloid in Alzheimer's disease

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PROJECT SUMMARY Alzheimer’s disease (AD) is the leading cause of dementia, affecting 6.2 million people in the United States and 44 million worldwide. These numbers are expected to quadruple by 2050, if no cure is found by then. AD features progressive neurodegeneration beginning in the hippocampus, leading to early loss of declarative hippocampal- dependent memory. The deposition of misfolded amyloid, a key pathological hallmark of AD preceding the onset of dementia by decades, is believed to be an initiating factor of the progressive neurodegeneration and memory loss. However, the underlying mechanisms remain unclear. Early in AD, amyloid deposition is accompanied by reduction of cerebral blood flow. Also, amyloid deposits are conspicuously found on the brain microvasculature, which results in impaired vasoactivity in response to stimulation. The collective evidence leads us to hypothesize that vascular amyloid impairs microvessel’s ability to regulate local blood oxygen delivery to meet the metabolic need of neurons in the hippocampus, causing early memory loss in AD. Further, we hypothesize that the amyloid- mediated, neurovascular pathology-driven memory decline in the hippocampus is reversible with improved blood oxygen delivery. Testing the hypotheses may offer new insights into AD pathogenesis, but it requires longitudinal microscopic assessments of neurovascular function in the hippocampus of AD mice with known memory status, which is largely beyond the reach of conventional benchtop microscopy techniques. To address this challenge, we propose to develop a bidirectional (imaging and manipulation) fiber interface for longitudinal and minimally invasive assessments of deep brain regions in rodents. Combining photoacoustic and fluorescence microscopy, this device (diameter: 230–420 µm) will enable concurrent imaging of amyloid deposition, microvascular function (blood oxygenation and flow), and neuronal activity in the hippocampus of AD mice. Moreover, building upon our recent progress in fiber-based deep brain stimulation and chemical delivery, this interface will also enable focal electrical stimulation to assess neurovascular coupling and local delivery of PGE2, a vasodilator, to examine the function of vascular smooth muscles and whether hippocampal blood oxygen supply is retrievable to counteract the amyloid-mediated focal hypoxia/ischemia and improve memory loss. In summary, the proposed study seeks to establish the direct and causal relationship between amyloid-mediated neurovascular dysfunction and memory loss in the hippocampus, where AD originates, through the development and application of a bidirectional deep brain interface. More broadly, altered neural-vascular interaction and misfolded protein aggregation have been associated with a wide range of brain diseases, including but not limited to AD. Enabling microscopic assessment and focal manipulation of neuronal activity, blood oxygen delivery, and pathological molecular processes in the rodent brain irrespective of depth, the bidirectional deep brain interface is expected to find broad applications in basic and translational brain research.