The interaction of recurrent axon collateral networks in the basal ganglia

We have proposed that the basal ganglia act as the central switching mechanism for the action selection system of the vertebrate brain. Simulation of our functional model of basal ganglia demonstrated that their output was consistent with this action selection hypothesis. Here we extend this model by incorporating anatomically-inspired local inhibitory axon collateral networks into two basal ganglia nuclei (globus pallidus and substantia nigra pars reticulata). Through simulation it is demonstrated that the basal ganglia’s ability to function as a selection mechanism is impaired by the individual addition of the collateral networks but slightly improved when they co-exist. Therefore, we predict the existence of local axon collaterals in the entopeduncular nucleus because of its functional equivalence with the substantia nigra pars reticulata.We conclude that the action selection hypothesis is supported by the continued functioning of the basal ganglia model as a switching mechanism following appropriate anatomically-inspired additions

Alzheimer amyloid Peptide aβ42 regulates gene expression of transcription and growth factors

The pathogenesis of Alzheimer's disease (AD) is characterized by the aggregation of amyloid-{beta} (A{beta}) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and A{beta} represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble A{beta}42 correlate with symptoms of AD, less is known about the biological activities of A{beta} peptides which are generated from the amyloid-{beta} protein precursor. An unbiased DNA microarray study showed that A{beta}42, at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic A{beta}42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide A{beta}42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble A{beta}42 and may represent useful early biomarkers

Clinical correlations with lewy body pathology in LRRK2-related Parkinson disease

IMPORTANCE: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of genetic Parkinson disease (PD) known to date. The clinical features of manifesting LRRK2 mutation carriers are generally indistinguishable from those of patients with sporadic PD. However, some PD cases associated with LRRK2 mutations lack Lewy bodies (LBs), a neuropathological hallmark of PD.We investigated whether the presence or absence of LBs correlates with different clinical features in LRRK2-related PD. OBSERVATIONS: We describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013.Among the different mutations, the LRRK2 p.G2019S mutation was most frequently associated with LB pathology. Nonmotor features of cognitive impairment/dementia, anxiety, and orthostatic hypotension were correlated with the presence of LBs. In contrast, a primarily motor phenotype was associated with a lack of LBs. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first report of clinicopathological correlations in a series of LRRK2-related PD cases. Findings from this selected group of patients with PD demonstrated that parkinsonian motor features can occur in the absence of LBs. However, LB pathology in LRRK2-related PD may be a marker for a broader parkinsonian symptom complex including cognitive impairment