Recent findings indicate that vascular risk factors and neurovascular dysfunction play integral roles in the pathogenesis of Alzheimer's disease. In addition to aging, the most common risk factors for Alzheimer's disease are apolipoprotein e4 allele, hypertension, hypotension, diabetes, and hypercholesterolemia. All of these can be characterized by vascular pathology attributed to conditions such as cerebral amyloid angiopathy and subsequent blood-brain barrier dysfunction. Many epidemiological, clinical, and pharmacotherapeutic studies have assessed the associations between such risk factors and Alzheimer's disease and have found positive associations between hypertension, hypotension, and diabetes mellitus. However, there are still many conflicting results from these population-based studies, and they should be interpreted carefully. Recognition of these factors and the mechanisms by which they contribute to Alzheimer's disease will be beneficial in the current treatment regimens for Alzheimer's disease and in the development of future therapies. Here we discuss vascular factors with respect to Alzheimer's disease and dementia and review the factors that give rise to vascular dysfunction and contribute to Alzheimer's disease. KeywordsAlzheimer's disease; apolipoprotein; blood-brain barrier; cholesterol; diabetes; hypertension; risk factorsThe prevalence of dementia, particularly Alzheimer's disease (AD), is increasing and it is one of the most important neurodegenerative disorders in the elderly. It is estimated that 5% to 10% of the elderly in the age range of 65 to 74 years are affected and that 25% to 50% of the elderly over the age of 85 years are affected. Of these cases, AD accounts for 50% to 60%, and the risk for AD doubles every 5 years after the age of 65 years.1 It is projected that by 2040, 81.1 million people will be affected worldwide with dementia,2 with frequencies for AD and vascular dementia (VaD) of 70% and 15%, respectively.3 The neuropathological © 2010 Mount Sinai School of Medicine Address Correspondence to: Dara L. Dickstein Department of Neuroscience Mount Sinai School of Medicine New York, NY dara.dickstein@mssm.edu. DISCLOSURES Potential conflict of interest: Samuel Gandy is currently a consultant to Diagenic, Pfizer/Janssen, and Amicus and was a consultant to Epix in the past. He also has an Investigator-initiated grant from Forest. NIH Public Access Author ManuscriptMt Sinai J Med. Author manuscript; available in PMC 2010 August 10. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript hallmarks of AD are intraneuronal protein aggregates of hyperphosphorylated tau protein [neurofibrillary tangles (NFTs)], aggregation of neurotoxic amyloid beta (Aβ) protein in the brain parenchyma and in blood vessel walls,4 and neuronal degeneration and loss. Currently, one of the prevailing theories of AD pathophysiology is the amyloid cascade hypothesis, which implicates Aβ as the key player in the formation of senile plaques and neuronal death. 4 However, recent evid...

Neurofibrillary tangles (NFTs) are composed of insoluble, hyperphosphorylated aggregates of the microtubule-associated protein tau and are present in various neurodegenerative diseases, including Alzheimer's disease (AD). To investigate how tau affects neuronal function during NFT formation and subsequent neurodegeneration, we examined the morphology, spine density, spine type, and spine volume of layer III pyramidal neurons from the prefrontal cortex of mice expressing wild-type human tau (htau) over time. There were no significant alterations in apical dendritic arbor length in 3-, 6-, and 12-month-old htau mice; however, 12-month-old mice exhibited more complex arborization patterns. In addition, we observed a shift in spine morphology with fewer mushroom and more thin spines in both apical and basal dendrites as a function of htau accumulation. Interestingly, there was an overall decrease in volume of spines from 3 to 12 months. However, the volume of mushroom spines decreased from 3 to 6 months and increased from 6 to 12 months. This increase in complexity and branching in 12-month-old mice and the increase of volume of mushroom spines may represent compensatory mechanisms in the remaining intact neurons. As such, the accumulation of phosphorylated tau over time may contribute to the cognitive decline observed in AD by affecting neuronal structure and synaptic properties. Such alterations in dendrites and spines may result in the deterioration of neuronal function observed in AD, and provide a morphologic substrate for the relationship between synaptic integrity and cognitive decline.

The diversity of receptor signaling is increased by receptor heteromerization leading to dynamic regulation of receptor function. While a number of studies have demonstrated that family A G-protein-coupled receptors are capable of forming heteromers in vitro, the role of these heteromers in normal physiology and disease has been poorly explored. In this study, direct interactions between CB1 cannabinoid and delta opioid receptors in the brain were examined. Additionally, regulation of heteromer levels and signaling in a rodent model of neuropathic pain was explored. First we examined changes in the expression, function and interaction of these receptors in the cerebral cortex of rats with a peripheral nerve lesion that resulted in neuropathic pain. We found that, following the peripheral nerve lesion, the expression of both cannabinoid type 1 receptor (CB1R) and the delta opioid receptor (DOR) are increased in select brain regions. Concomitantly, an increase in CB1R activity and decrease in DOR activity was observed. We hypothesize that this decrease in DOR activity could be due to heteromeric interactions between these two receptors. Using a CB1R-DOR heteromer-specific antibody, we found increased levels of CB1R-DOR heteromer protein in the cortex of neuropathic animals. We subsequently examined the functionality of these heteromers by testing whether low, non-signaling doses of CB1R ligands influenced DOR signaling in the cortex. We found that, in cortical membranes from animals that experienced neuropathic pain, non-signaling doses of CB1R ligands significantly enhanced DOR activity. Moreover, this activity is selectively blocked by a heteromer-specific antibody. Together, these results demonstrate an important role for CB1R-DOR heteromers in altered cortical function of DOR during neuropathic pain. Moreover, they suggest the possibility that a novel heteromer-directed therapeutic strategy for enhancing DOR activity, could potentially be employed to reduce anxiety associated with chronic pain.

In the primate prefrontal cortex (PFC), the functional maturation of the synaptic connections of certain classes of GABA neurons is very complex. For example, the levels of both pre- and post-synaptic proteins that regulate GABA neurotransmission from the chandelier class of cortical interneurons to the axon initial segment (AIS) of pyramidal neurons undergo marked changes during both the perinatal period and adolescence in the monkey PFC. In order to understand the potential molecular mechanisms associated with these developmental refinements, we quantified the relative densities, laminar distributions, and lengths of pyramidal neuron AIS immunoreactive for ankyrin-G, ßIV spectrin, or gephyrin, three proteins involved in regulating synapse structure and receptor localization, in the PFC of rhesus monkeys ranging in age from birth through adulthood. Ankyrin-G- and ßIV spectrin-labeled AIS declined in density and length during the first six months postnatal, but then remained stable through adolescence and into adulthood. In contrast, the density of gephyrin-labeled AIS was stable until approximately 15 months of age and then markedly declined during adolescence. Thus, molecular determinants of the structural features that define GABA inputs to pyramidal neuron AIS in monkey PFC undergo distinct developmental trajectories with different types of changes occurring during the perinatal period and adolescence. In concert with previous data, these findings reveal a two-phase developmental process of GABAergic synaptic stability and GABA neurotransmission at chandelier cell inputs to pyramidal neurons that likely contributes to the protracted maturation of behaviors mediated by primate PFC circuitry.