Thomas Van Groen, Ph.D.

tgroenAssociate Professor

Primary Department Affiliation
: Cell, Developmental and Integrative Biology
Primary Research Area: Neurodegeneration and Neurodegenerative Disorders
Neurotransmitter and Neurotrophin Receptors and Cell Signaling
Learning, Memory, and Synaptic Plasticity
Neurodevelopment and Developmental Disabilities
Systems Neuroscience and Vision

Email: This email address is being protected from spambots. You need JavaScript enabled to view it.
Phone: 205.934.5940

Recent Publications

Overview of Current Research

Amyloid angiopathy in cognitive dysfunction and Alzheimer's disease

In addition to the well-known accumulation of amyloid beta (Aβ) in neuropil plaques and intracellular sites, Alzheimer's disease (AD) is associated with substantial Aβ deposition in the cerebral vasculature. Whereas, clearly, cerebrovascular disease is not the sole cause of AD, mounting evidence indicates that cerebrovascular amyloid angiopathy (CAA) contributes to some aspects of the cognitive impairments associated with AD. These findings have led to the hypothesis that CAA contributes to neuronal dysfunction and thus cognitive impairment, possibly through brain hypoperfusion. However, there is a temporal overlap between the deposition of Aβ in neuropil and cerebrovasculature, making it difficult to separate the relative contributions to AD dementia from CAA vs. neuropil Aβ. Our recent preliminary studies examining the course of amyloidosis in AD model mice indicate that CAA often develops prior to neuropil Aβ deposition. Further, some of the available transgenic (Tg) AD models exhibit quite different levels of vascular versus neuropil deposits. Finally, neuropil Aβ develops more extensively and earlier in female vs male mice. Thus, the following studies are designed to use the temporal separation and quantitative differences in Aβ deposition in the blood vessel wall versus neuropil, to test the hypothesis that CAA contributes to cognitive dysfunction and pathology in AD.

We are testing the prediction that 1) CAA precedes neuropil Aβ deposition and 2) compared to the course of Aβ deposition in neuropil, CAA is more closely linked in time to the onset of cognitive impairment. 3) We also are examining the hypothesis that Aβ deposition in blood vessels is associated with altered blood flow, oxidative stress and inflammation that in turn will lead to cognitive deficits and finally, 4) we will study whether pharmaceutical reduction of cerebrovascular inflammation significantly reduces the development of CAA and brain Aβ deposition and attenuates the development of cognitive dysfunction. We propose to use simultaneous quantification of CAA, and extra- and intra-cellular Aβ deposition, and cortical blood flow in conjunction with systematic analyses of behavioral and pathological markers in two different Tg AD models (expressing high and low degrees of CAA), to test these working hypothesis.

The proposed studies will produce the first systematic time course study relating the deposition of Aβ in the vascular and other compartments of the brain to development of cognitive dysfunction. The multidisciplinary experience of our group in studies of hippocampal system anatomy/physiology, vascular function and detailed behavioral and pathological analyses in Tg animals places us in an advantageous position to test the increasingly important possibility that CAA is a significant contributor to cognitive dysfunction and neuropathology in Tg AD models and in humans.

Hypertension in cognitive dysfunction and Alzheimer's disease

Hypertension is a risk factor for stroke, cardiovascular disorders, and vascular dementia, and the incidence of these diseases grows with increasing blood pressure. Recent studies have shown that hypertension is also a risk factor for Alzheimer's disease (AD). AD is associated with the accumulation of amyloid beta (Aβ) in plaques in the brain parenchyma but also with substantial amyloid β deposition in the cerebral vasculature. Furthermore, it has been demonstrated that AD patients have cerebral hypoperfusion and hypoactivity. Clearly, cerebrovascular disease is not the sole cause of AD, but mounting evidence indicates that changes in the cerebrovasculature and in cerebral blood flow do contribute to the cognitive dysfunction associated with AD. For instance, recent studies have indicated that cerebral blood vessel reactivity is impaired in Tg AD model mice. The brain renin-angiotensin system plays an important role in the regulation of the cerebral blood pressure and blood flow, but with increasing age (and during the development of CAA) this regulation is altered. This modifies the cerebral circulation such that sustained hypoperfusion or oligemia is impacted upon the aging process to induce augmented pathology. Our preliminary studies indicate that aged Tg AD model mice exhibit decreased cerebral blood flow and blood volume when significant amyloid β depositions are present. Together, these findings have led to the hypothesis that sustained hypertension will lead to decreased functional hyperemia in the brain, and that this contributes to brain hypoperfusion which adds to the cognitive impairments of AD. Further, decreased blood flow will concurrently lead to increased amyloid β deposition in the brain due to decreased clearance of amyloid β. Thus, our studies are designed to test the hypothesis that long-term untreated hypertension will lead to perturbed vascular function, oligemia, and increased cognitive dysfunction and pathology in AD model mice.

Treatment of amyloid pathology and cognitive deficits with small D-peptides.

Several lines of evidence, including genetics, have provided strong evidence for a central role of the amyloid-β-peptide (Aβ) in the pathogenesis of Alzheimer’s disease (AD). Whereas it now seems unlikely that plaques contribute significantly to the cognitive deficits of AD, it is becoming more and more probable that Aβ oligomer peptides are the culprit.   Thus, inhibition of Aβ oligomerization in the brain is an important target for AD therapy. We tested a D-enantiomeric amino acid peptide (D3) with strong and specific binding properties for Aβ42, and we have demonstrated that the peptide has a strong influence on Aβ oligomerization, disaggregation and cytotoxicity in vitro and in vivo. We have created a new D-enantiomeric amino acid peptide, a dipeptide (i.e., D3D3) with even stronger and more specific binding properties for oligomeric Aβ42. We have preliminary evidence that in vitro, it significantly reduces amyloid β oligomerization.  We propose to use simultaneous quantification of Aβ deposition and Aβ levels in conjunction with detailed analyses of behavioral and pathological markers in a Tg AD model to test this working hypothesis. The proposed studies will yield a systematic time course study relating the prevention of the formation of Aβ oligomers in the brain to the development of cognitive dysfunction. We propose to infuse the peptide in the brain and i.p. using Alzet minipumps for two months and analyze cognitive outcome, Aβ deposition and Aβ levels, and levels of inflammatory markers.  The peptide has similar characteristics to D3, therefore we expect it to significantly reduce Aβ pathology and cognitive deficits, therefore providing a basis for a new therapeutic approach.

Furthermore I am the Technical Director of the UAB Behavioral Assessment Core, that provides behavioural testing for mice and rats.  We have a large number of tests available, and a technician who can help with the testing.  Assistance with data analysis and advice for testing is available, and a library of papers and handbooks is available through the Core.

Thank you for using the UAB Neuroscience Behavioral Assessment Core. Please give appropriate acknowledgement to P30 NS47466 in your papers.