AD is a neurodegenerative disease of complex etiology (29, 30). The formation of neurofibrillary tangles (NFT), neuropil threads, and senile plaques have been implicated in the onset and development of the disease, but the relative causal weight of these and other factors in sporadic AD continues to be debated (30, 31). Although initiation and progression of AD may thus be multifactorial, it has been noted that incidence and regional distribution of NFT are most closely associated with the clinical manifestations of the disease (32, 33). NFT formation is the result of the accumulation of altered components of the neuronal cytoskeleton (34), and it has been suggested that “clogging” of neuronal processes and disruption of long-distance transport may underlie at least some of the cytopathological changes that characterize the disease (19).
We suggest that such cellular changes on one hand and deregulated expression and transport of dendritic RNAs on the other may be causally interrelated in AD. It has recently been speculated that non-protein-coding RNAs may be involved in AD (35), and we now show that expression of dendritic BC200 RNA, which is a translational repressor (3, 5), is differentially regulated in normal aging and in AD. In normal aging, BC200 levels in the neocortex decrease substantially after age 50. Because BC RNAs are prominently located throughout dendrites and at synapses (1, 2, 8), the substantial decline of BC levels may reflect the progressive atrophy of synaptodendritic structures that has previously been observed in normal aging (23, 36–39).
In AD, synapse loss and dendritic regression are substantial (40), but these degenerative changes are accompanied by significant dendritic sprouting and remodeling, often in the same neuron (30, 41, 42). Such reactive developments may be of a compensatory nature, directed at maintaining connectivity and plasticity. In one possible scenario, we therefore suggest that the substantially higher BC200 levels in AD, as compared with those in normal aging, may represent a molecular compensatory effort. If BC200 RNA is needed at the synapse for local translational control, its loss from synaptodendritic domains as the result of dendritic regression and clogging in AD may trigger compensatory mechanisms that result in the increased production of the RNA.
Increased synthesis of key synaptodendritic components may be an appropriate response in situations in which cargoes are not effectively delivered to postsynaptic sites. It may, at least initially or partially, be successful in overcoming moderate dendritic clogging that is caused by altered cytoskeletal components. Over time, however, such response may prove inadequate if further accumulation of cytoskeletal debris creates “roadblocks” that RNAs with dendritic destinations are no longer able to traverse. At this point, relative BC200 levels would begin to decrease in dendrites but increase in somata. In such cases, efforts to compensate would have failed because even increased production could no longer ensure that the RNA reaches its dendritic target sites. Transport deficits have previously been implicated in the progression of AD (18–20), and impaired microtubule-dependent transport, coupled with beginning axonal and dendritic blockage, may be an early event in AD that could eventually result in the local generation of amyloid-β peptides and thus in amyloid deposition (17).
Alternative scenarios are possible or even likely. Instead of, or in addition to, being reactive–compensatory to cytoskeletal degeneration, imbalances in the somatodendritic distribution of BC200 RNA could be causative because they may lead to aberrant local translational control. BC200 RNA contains a kink turn motif of the KT-58 subtype that has been implicated in dendritic transport of BC RNAs (9, 43). Because only slight perturbations of the kink turn motif architecture are sufficient to disrupt targeting (9), it is conceivable that single-nucleotide mutations in this region may prevent delivery of the RNA along the dendritic extent. Consequences would be twofold: compensatory elevation of BC200 transcription in an attempt to overcome dendritic delivery block and poor translational control in synaptodendritic domains. Consistent with this model, altered relative BC200 levels become manifest at a very early time point in the course of AD, possibly before clinical signs become detectable (44, 45).
A gradual worsening of somatodendritic BC200 imbalances may over time set off a self-reinforcing feed–forward cycle. Inadequate translational regulation in dendrites may lead to cytoskeletal overproduction and local dysfunction (16), which in turn would hinder the transport of mRNAs and protein synthetic machinery to postsynaptic target sites. In line with this concept, levels of somatodendritic RC3 mRNA have been shown to be significantly diminished in dendritic regions of AD brains (46). Having been disrupted in this manner, the system would find itself on a slow but accelerating course toward eventual catastrophe, manifesting as synaptic or plasticity failure (17, 30, 47–49). At the same time, increased perikaryal levels of BC200 RNA may inappropriately repress somatic protein synthesis and thus precipitate or exacerbate degenerative changes. We anticipate that future work, directed at the understanding of neuronal RNA transport and local translational control mechanisms, will be able to establish the respective contributions of the causative and reactive–compensatory scenarios.
The study samples come from the Adult Changes in Thought (ACT) study, a longitudinal research effort led by Eric B. Larson, M.D., M.P.H., and Paul K. Crane, M.D., M.P.H., of the Kaiser Permanente Washington Health Research Institute (KPWHRI) (formerly known as Group Health Research Institute) and the University of Washington School of Medicine to collect data on thousands of aging adults, including detailed information on their health histories and cognitive abilities.
“This collaboration with the Allen Institute for Brain Science has allowed us to gain insights never before possible into the relationships between neuropathology, gene expression, RNA quality, and clinical features tracked in the ACT study over more than 20 years,” says Larson, who has led the National Institute of Aging-supported study from its start in 1986 and is Vice President for Research and Health Care Innovation at Kaiser Permanente Washington.
During this generative sleep stage, the strengths of the feedforward synaptic … in the sense that only small changes are made during any one wake–sleep cycle. … sleep, the visual cortex is driven by brain-stem activity and the hippocampus …
So, to the degree that the hippocampal output during ripples originates in … in the prefrontal cortex and spreading through the whole neocortex and brain issue a … a feed forward manner favors the occurrence of another slow oscillation cycle …
… transmission in the piriform cortex, with a much weaker effect on feedforward … in the hippocampusgo much higher than ACh levels in neocortex (Marrosu et al., … rapid changes in modulatory dynamics within each cycle of the theta rhythm.
1): 1) feed–forward inhibition, in which excitatory inputs from extrinsic brain regions recruit local inhibitory … Feed–forward inhibition in neocortex and hippocampus …. This cycle then repeats to propagate seizure activity to the next microcircuit.
Ahn SM, Freeman WJ (1974) Steady-state and limit cycle activity of mass of … of functionally segregated circuits linking basal ganglia and cortex. … Alger BE, Nicoll RA (1982) Feed–forward dendritic inhibition in rat hippocampal pyramidal cells …
May 16, 2016 – The lateral entorhinal cortex (LEC) computes and transfers olfactory … Here we established LEC connectivity to upstream and downstream brain … RE+ neurons provide feedforwardprojections to the hippocampus while …… All animals were housed singly or in pairs and were kept on a 12 h light/dark cycle.
From Neurons to Mind Christoph von der Malsburg, William A. Phillips, Wolf Singer … and Transfer at theHippocampus–Entorhinal– Neocortical Interface György Buzsáki … the multisynaptic feedforward loops of the entorhi- nal–hippocampal system, … In each oscillatory cycle, recruitment of principal neurons is temporally …
(A) Multiple loops of the hippocampal-entorhinal (EC) circuits. … computation in successive layers of the EC-hippocampus (mainly) feedforward loop. … the main direction of information flow, withneocortical– hippocampal transfer taking place … Neurons that discharge within the time period of the gamma cycle (10–30 msec) …
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