Cytochemical, anatomical, pathological and cognitive evidence indicates that brain dysfunction in Alzheimer's disease (AD) does not involve every neuronal system or affect all cognitive functions indiscriminately. This important feature of the pathophysiology of AD has so far been addressed in terms of the connections among structures served by projection neurons, while the involvement of the internal organization of the cerebral cortex - served mostly by local circuit neurons (LCN) - has received considerably less attention. Cortical LCN appear to belong to several classes that are region-specific and morphologically, chemically, and functionally distinct each of which may be selectively affected or spared in AD. I plan to address this topic in AD and dementia with cortical Lewy bodies (DCLB; which is characterized by prominent involvement of LCN), as a continuation of my long-standing interest in the organization and pathology of LCN in the cerebral neocortex, using my experience in histochemistry, immunocytochemistry, and in situ hybridization. These methods are uniquely suited to study LCN in the cortex of victims of dementia and in nonhuman primates. Most human tissue for light and electron microscopic analysis will be obtained from autopsy with short postmortem delays. I will focus on LCN with unique molecular phenotypes' (neuroactive peptides, NADPH diaphorase, tyrosine hydroxylase) in modular compartments within sensory, motor and association neocortices. Key aspects of the organization of these neurons will be characterized in monkeys, verified in human normative and control material, and their involvement in AD and DCLB lesions analyzed. One emphasis will be on types of LCN that occur only in certain cortical areas, and therefore are possibly specialized for unique information processing tasks. For example, types of LCN situated in temporal regions may be more severely affected than others in primary motor or sensory areas. I will also investigate potentially affected novel populations of LCN that may contain monoamines and acetylcholine, substances formerly believed to originate exclusively from subcortical neurons which may be involved in AD. This may help to elucidate and modify the role of LCN in cognitive functions and in the pathophysiology of AD and DCLB. Given the increasing amount of pharmacologically relevant information on neurotransmitters that are present predominantly in LCN, the study of these neurons is likely to become clinically important in the event that palliative therapy for AD and other dementias is developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029856-03
Application #
3416768
Study Section
Pathology A Study Section (PTHA)
Project Start
1991-08-01
Project End
1994-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Kuljis, Rodrigo O; Salkovic-Petrisic, Melita (2011) Dementia, diabetes, Alzheimer's disease, and insulin resistance in the brain: progress, dilemmas, new opportunities, and a hypothesis to tackle intersecting epidemics. J Alzheimers Dis 25:29-41
Kuljis, R O; Chen, G; Lee, E Y et al. (1999) ATM immunolocalization in mouse neuronal endosomes: implications for ataxia-telangiectasia. Brain Res 842:351-8
Kuljis, R O; Aguila, M C (1999) Neurodegeneration in ataxia-telangiectasia is caused by horror autotoxicus. Med Hypotheses 52:377-82
Aguila, M C; Kuljis, R O (1999) Degeneration of NO-synthesizing cerebrocortical neurons in transgenic mice expressing mutated superoxide dismutase is not due to elevated nitric oxide levels. Brain Res 816:241-4
Kuljis, R O; Xu, Y; Aguila, M C et al. (1997) Degeneration of neurons, synapses, and neuropil and glial activation in a murine Atm knockout model of ataxia-telangiectasia. Proc Natl Acad Sci U S A 94:12688-93
Kuljis, R O; Tikoo, R K (1997) Discontinuous distribution of senile plaques within striate cortex hypercolumns in Alzheimer's disease. Vision Res 37:3573-91
Kuljis, R O; Schelper, R L (1996) Alterations in nitrogen monoxide-synthesizing cortical neurons in amyotrophic lateral sclerosis with dementia. J Neuropathol Exp Neurol 55:25-35
Kuljis, R O (1994) Lesions in the pulvinar in patients with Alzheimer's disease. J Neuropathol Exp Neurol 53:202-11
Fischer, H C; Kuljis, R O (1994) Multiple types of nitrogen monoxide synthase-/NADPH diaphorase-containing neurons in the human cerebral neocortex. Brain Res 654:105-17