Rush University Medical Center, USA
His research is directed towards the development of treatment approaches for diseases of the brain. In this regard, he participated in clinical trials using gene therapy to treat Alzheimer’s and Parkinson’s disease in collaboration with Ceregene, Inc. Heam currently working with Medtronics and Neurophage to develop treatments for Alzheimer’s disease (AD). Currently,heis a co-leader on a National Institute forMental Health (NIMH) grant to test the ability of choline as a treatment of Down’s syndrome (DS) using an animal model of this disease
The cortical mantle receives a massive cholinergic innervation arising from the nucleus basalis of Meynert (NBM) that is progressively vulnerable during the onset of dementia. However, the role that intraneuronal tau, cortical amyloid and neurotrophic dysfunction play in the unique vulnerability of the cholinergic basal forebrain (CBF) cortical projection network remains unclear. We used biochemical and immunohistochemical procedures to evaluate amyloid levels, cholinergic activity, proNGF/receptors and down stream signaling pathways in the precueus cortex (a default memory network hub) which displays amyloid pathology in preclinical AD in postmortem tissues harvested from no cognitive impairment (NCI), mild cognitive impairment (MCI) and AD cases. Pre-tangle events determined by pS422 immunostaining revealed positive NBM cholinergic neurons and neuropil threads (NT) prior to frank NFT deposition in MCI, which associated with cognitive decline. Despite accumulating amyloid burden, cholinergic enzyme activity was stable in MCI but declined in AD when amyloid levels were elevated compared with MCI precuneus. Precuneus proNGF and p-JNK/JNK ratio protein levels increased only in AD whereas TrkA and p75NTR receptor levels were unchanged. Interestingly, ventricular proNGF CSF levels marked the progression from NCI to MCI and AD and discriminated NCI from AD in lumbar CSF. Our findings suggest that NBM pretangle cell and NT pathology drive early cognitive decline. Despite amyloid deposition cholinergic activity and proNGF levels remained stable suggesting that this cortical region is resilient to amyloid toxicity early in disease onset. Finally, proNGF expression may be a novel biomarker for the onset of dementia.