Article

Cholinergic deafferentation of the rabbit cortex: a new animal model of Abeta deposition.

Sun Health Research Institute, Sun City, AZ 85351, USA.
Neuroscience Letters (impact factor: 2.11). 04/2000; 283(1):9-12. pp.9-12
Source: PubMed

ABSTRACT Brain deposition of the amyloid beta-peptide (Abeta) is a critical step in the pathogenesis of Alzheimer's disease (AD) and human cerebral amyloid angiopathy (CAA). A small fraction of AD and CAA cases are caused by gene mutations leading to increased production and deposition of Abeta, but for the majority, there is no known direct genetic cause. We have hypothesized that Abeta deposition in these sporadic cases occurs as a result of cortical cholinergic deafferentation. Here we show that cortical cholinergic deafferentation, induced in rabbits by a selective immunotoxin, leads to Abeta deposition in cerebral blood vessels and perivascular neuropil. Biochemical measurements confirmed that lesioned animals had 2.5- and 8-fold elevations of cortical Abeta40 and Abeta42, respectively. Cholinergic deafferentation may be one factor that can contribute to Abeta deposition.

0 0
 · 
0 Bookmarks
 · 
19 Views
  • Source
    Article: Cholinergically mediated augmentation of cerebral perfusion in Alzheimer's disease and related cognitive disorders: the cholinergic-vascular hypothesis.
    Jurgen A H R Claassen, René W M M Jansen
    [show abstract] [hide abstract]
    ABSTRACT: The treatment of Alzheimer's disease (AD) with cholinesterase inhibitors (ChEIs) is based on the cholinergic hypothesis. This hypothesis fails to account for the global nature of the clinical effects of ChEIs, for the replication of these effects in other dementias, and for the strong and unpredictable intraindividual variation in response to treatment. These findings may be better explained by the premise that ChEIs primarily act by augmenting cerebral perfusion: the cholinergic-vascular hypothesis. This article will review the evidence from preclinical and clinical investigations on the vascular role of the cholinergic neural system. The clinical relevance of this hypothesis is discussed with respect to its interactions with the vascular and amyloid hypotheses of AD. Implications for treatment are indicated. Finally, we propose that the role of the cholinergic system in neurovascular regulation and functional hyperemia elucidates how the cholinergic deficit in AD contributes to the clinical and pathological features of this disease.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 04/2006; 61(3):267-71. · 4.60 Impact Factor
  • Source
    Article: Broader considerations of higher doses of donepezil in the treatment of mild, moderate, and severe Alzheimer's disease.
    Camryn Berk, Marwan Sabbagh
    [show abstract] [hide abstract]
    ABSTRACT: Donepezil, a highly selective acetylcholinesterase inhibitor (AChEI), is approved as a symptomatic treatment mild, moderate, and severe Alzheimer's disease (AD). Donepezil exerts its treatment effect through multiple mechanisms of action including nicotinic receptor stimulation, mitigation of excitotoxicity, and influencing APP processing. The use of donepezil at higher doses is justified given the worsening cholinergic deficit as the disease advances. Donepezil has been investigated in several clinical trials of subjects with moderate-to-severe AD. While the side effects are class specific (cholinergically driven), demonstrable benefit has been shown at the 10 mg dose and the 23 mg doses. Here, we review the clinical justification, efficacy, safety, and tolerability of use of donepezil in the treatment of moderate-to-severe AD.
    International journal of Alzheimer's disease. 01/2012; 2012:707468.
  • Source
    Article: Morphological and pathological evolution of the brain microcirculation in aging and Alzheimer's disease.
    Jesse M Hunter, Jason Kwan, Michael Malek-Ahmadi, Chera L Maarouf, Tyler A Kokjohn, Christine Belden, Marwan N Sabbagh, Thomas G Beach, Alex E Roher
    [show abstract] [hide abstract]
    ABSTRACT: Key pathological hallmarks of Alzheimer's disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular "dysfunction" compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD.
    PLoS ONE 01/2012; 7(5):e36893. · 4.09 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

8-fold elevations
 
Alzheimer's disease
 
amyloid beta-peptide
 
Biochemical measurements
 
Brain deposition
 
CAA
 
CAA cases
 
cerebral blood vessels
 
Cholinergic deafferentation
 
cortical Abeta40
 
cortical cholinergic deafferentation
 
critical step
 
gene mutations
 
human cerebral amyloid angiopathy
 
known direct genetic cause
 
lesioned animals
 
pathogenesis
 
small fraction
 
sporadic cases