Current Alzheimer Research - Volume 10, Issue 10, 2013

Ever since amyloid-β (Aβ) peptides were first identified in cerebral plaques in patients with Alzheimer's disease (AD), much research work has focused on the complex mechanisms through which these peptides are synthesized, transported and degraded. Although new information emerges on a regular basis, we consider that the importance of the blood-brain barrier (BBB) in the pathogenesis of AD has been underestimated. In fact, there are a number of obstacles that make it difficult to convince specialists in AD that the BBB indeed plays a key role in this disease: these include the complex physiology of the BBB and the technical difficulty of studying the barrier in vivo and reproducing its main properties in vitro. With these considerations in mind, the present review sets out summarize our current knowledge about the physiology of the BBB and describe recent research findings on the barrier's role in Aβ peptide proteostasis and thus in the mechanism of AD.

Amyloid-β (Aβ) is known as the most prominent core protein in Alzheimer's Disease (AD) senile plaques. Although research has focused mainly on Aβ40 and Aβ42 as potential cerebrospinal fluid (CSF) biomarkers, a range of Aβ peptides with variable lengths has been demonstrated in the brains and CSF of AD patients. Recently, it has been found that the Aβ43 peptide may be more abundant than previously assumed, could therefore play an important role in AD pathophysiology, and hence also function as putative biomarker. In this study the value of CSF Aβ43 in AD diagnosis was investigated. Aβ43 levels in CSF were highly correlated with Aβ42 levels. Furthermore, in differentiation of AD from nondemented controls and from patients with Lewy body dementia and frontotemporal dementia, Aβ43 had an equal diagnostic value as Aβ42, both as a single biomarker and in combination with total and phosphorylated tau. In conclusion, quantification of Aβ43 in CSF does not add novel diagnostic information to the differential diagnosis of AD compared to existing biomarkers.

Oxidative stress is implicated in the pathogenesis of neurodegenerative diseases, including sporadic Alzheimer´s disease (AD). Mitochondrial DNA (mtDNA) deletions are markers of oxidative damage and increase with age. To unravel the impact of mtDNA damage on AD development, we analyzed mtDNA deletion levels in diverse neuronal cell types of four brain regions (hippocampal CA1 and CA2 regions, nucleus tractus spinalis nervi trigemini, and the cerebellum) that exhibit differing levels of vulnerability to AD related changes at progressive Braak stages compared with age-matched controls. Neurons from these four brain regions were collected using laser microdissection, and analyzed using quantitative polymerase chain reaction (qPCR). Although, no correlation between mtDNA deletion levels and AD progression were found, the data revealed regional and cell type specific selective vulnerability towards mtDNA deletion levels. In conclusion, unexpected results were obtained as granule cells from the cerebellum and neurons from the nucleus tractus spinalis nervi trigemini of the brain stem displayed significant higher mtDNA deletion levels than pyramidal cells from hippocampal CA1 and CA2 region in age and AD.

The Alzheimer’s disease “inflammation hypothesis” has emerged only recently, suggesting the risk of developing AD might be influenced by variants of genes encoding for inflammatory mediators. In order to investigate in this direction, genomic DNA from 194 Italian AD cases and 454 healthy controls matched by gender and ethnicity was analyzed for the Receptor for Advanced Glycation End products (RAGE, HLA class III-centromere portion) -374 and - 429 SNPs and for the Tumor Necrosis Factor-alpha (TNF-α, HLA class III-telomere portion) -857, -308 and -238 SNPs by RFLP and Real Time PCR. Our data show statistically significant deviations between AD patients and healthy controls concerning RAGE -374 SNP genotype (TT: p=0.0084) and allele (T, A: p=0.0081) frequencies; TNF-α -308 SNP AA genotype (p=0.0433) and TNF-α -238 SNP genotype (GG: p=0.0138) and allele (G, A: p=0.0151) frequencies. Furthermore, significant differences between the study groups and regarding RAGE TC (p=0.05) and AC (p=0.009) haplotypes are present, while TNF-α haplotype reconstruction point out a statistically significant difference between patients and controls regarding AGG haplotype (p=0.002). Finally, from the combination of the individually significant SNPs of the two genes (RAGE -374, TNF-α -238 and -308) we performed an HLA class III haplotype reconstruction finding significant differences between AD subjects and controls regarding the TAG (p=0.019) and TGA (p=0.008) haplotypes. The implication of these haplotypes with the disease points to a possible involvement of entire HLA class III region in AD susceptibility.

Soluble β-amyloid peptides (Aβ) and small Aβ oligomers represent the most toxic peptide moieties recognized in brains affected by Alzheimer's disease (AD). Here we provide the first evidence that specific St. John’s wort (SJW) extracts both attenuate Aβ-induced histopathology and alleviate memory impairments in APP-transgenic mice. Importantly, these effects are attained independently of hyperforin. Specifically, two extracts characterized by low hyperforin content (i) significantly decrease intracerebral Aβ42 levels, (ii) decrease the number and size of amyloid plaques, (iii) rescue neocortical neurons, (iv) restore cognition to normal levels, and (iv) activate microglia in vitro and in vivo. Mechanistically, we reveal that the reduction of soluble Aβ42 species is the consequence of a highly increased export activity in the bloodbrain barrier ABCC1transporter, which was found to play a fundamental role in Aβ excretion into the bloodstream. These data (i) support the significant beneficial potential of SJW extracts on AD proteopathy, and (ii) demonstrate for the first time that hyperforin concentration does not necessarily correlate with their therapeutic effects. Hence, by activating ABC transporters, specific extracts of SJW may be used to treat AD and other diseases involving peptide accumulation and cognition impairment. We propose that the anti-depressant and anti-dementia effects of these hyperforin-reduced phytoextracts could be combined for treatment of the elderly, with a concomitant reduction in deleterious hyperforin-related side effects.

Cholinergic precursors have represented the first approach to counter cognitive impairment occurring in adultonset dementia disorders. These compounds were early leaved because their clinical efficacy was not clearly demonstrated. This is probably not true for some choline-containing phospholipids including choline alphoscerate. Choline alphoscerate increases the release of acetylcholine in rat hippocampus, facilitates learning and memory in experimental animals, improves brain transduction mechanisms and decreases age-dependent structural changes occurring in rat brain areas involved in learning and memory. The compound exerts neuroprotective effects in models of altered cholinergic neurotransmission and of brain vascular injury. In clinical studies choline alphoscerate improved memory and attention impairment, as well as affective and somatic symptoms in dementia disorders. An ongoing trial indicates that association between the acetylcholinesterase inhibitor donepezil and choline alphoscerate is accompanied by an improvement in several cognitive tests superior to that induced by donepezil alone. It is suggested that this association may represent a therapeutic option to prolong beneficial effects of cholinergic therapies in Alzheimer's disease patients with concomitant ischemic cerebrovascular disorders. In summary, choline alphoscerate has significant effects on cognitive function with a good safety profile and tolerability. Although limited both in terms of size of the samples investigated and of the length of treatment, preclinical and clinical results presented suggest that cognitive enhancing capabilities of choline alphoscerate merit of being further investigated in appropriate trials.

Patients with amnestic mild cognitive impairment (aMCI) often display deficits in episodic memory. Amnestic MCI is now recognized as a prodromal form of Alzheimer's disease. Various aMCI clinical subtypes have been identified as ingle-domain (SD) or multi-domain (MD). The various subtypes represent heterogeneous syndrome indicating the probability of progression to AD, impaired cognitive domains and so on. To examine the characteristics of brain regions of aMCI subtypes is likely to be important for early diagnosis and prediction to AD. This study investigated brain functional activation and hippocampal atrophy during a visually complex scene encoding in 20 individuals with aMCI-SD, 14 individuals with aMCI-MD and 25 healthy controls. During the encoding task, aMCI-MD patients had reduced activation in right superior medial frontal, right inferior and middle temporal, right middle occipital and left inferior frontal regions compared to controls. The different active brain regions between aMCI-MD and aMCI-SD patients are the right middle occipital and left middle cingulum regions. The aMCI-MD group had significantly lower left hippocampus volumes compared to the aMCI-SD group and controls, but there was no difference between aMCI-SD patients and the control group in terms of left hippocampus atrophy. The findings provide evidence that aMCI may represent a heterogeneous group. The aMCI-MD patients displayed more severe hippocampcal atrophy and fMRI activation changes than aMCI-SD. The aMCIMD may represent a more advanced prodromal stage of AD.

Previous reports suggest that brain white matter changes, a surrogate for small vessel disease, are related to cerebral amyloid angiopathy (CAA). However, this relationship has not been explored in population-based studies or in the oldest old (>85 years of age). We studied the relationships between white matter hyperintensities (WMH) determined by post-mortem magnetic resonance imaging (MRI) and neuropathologically assessed CAA in demented and nondemented subjects enrolled in the prospective community-based Finnish Vantaa 85+ Study. In this analysis, we evaluated scans and brain samples from 123 subjects (86% women) with a mean age of 90.6 years. We found CAA to be present in 63% of the 123 subjects, whereas WMH was present in 74%, and dementia in 59%. The presence of WMH of any severity did not relate to the presence or the degree of CAA severity, irrespective of the dementia status of the subjects. Furthermore, multivariate regression analysis showed a clear association between CAA and dementia but WMH was not related to dementia in this very old sample. We conclude that severe WMH may not be determined by CAA in this very elderly population.

Mild cognitive impairment (MCI) could be an auspicious candidate for an early marker of a beginning dementia. However, although MCI is accepted as a heterogeneous condition by now, performance testing or diagnosis is often based on a limited number of cognitive tests. Furthermore, there is still disagreement about the necessity to include subjective cognitive complaints as a diagnostic criterion. The current study intends to examine the character of MCI when diagnosis is based upon multiple cognitive domains and does not require the presence of subjective complaints. 130 subjects from the HelMA (Helmholtz Alliance for Mental Health in an Ageing Society) longitudinal study completed a comprehensive neuropsychological test-battery and were diagnosed as either normally-ageing controls or patients with MCI. The prevalence rate of MCI was as high as 46.2%, hereby exceeding most estimates of other studies. Patients with MCI performed worse than controls in each of the 29 administered tests with memory being the predominant impaired cognitive domain. Surprisingly, there was no single patient with a purely non-amnestic impairment, considerably contradicting hitherto existing studies. The rather different distribution of impairment and prevalence rate emphasizes the demand of testbatteries including all cognitive domains so that inferences about MCI are as all-encompassing as possible.

The Self-reference effect (SRE) on long-term episodic memory and autonoetic consciousness has been investigated in young adults, scarcely in older adults, but never in Alzheimer's patients. Is the functional influence of Selfreference still present when the individual's memory and identity are impaired? We investigated this issue in 60 young subjects, 41 elderly subjects, and 28 patients with Alzheimer's disease, by using 1) an incidental learning task of personality traits in three encoding conditions, inducing variable degrees of depth of processing and personal involvement, 2) a 2- minute retention interval free recall task, and 3) a 20-minute delayed recognition task, combined with a remember-know paradigm. Each recorded score was corrected for errors (intrusions in free recall, false alarms in recognition, and false source memory in remember responses). Compared with alternative encodings, the Self-reference significantly enhanced performance on the free recall task in the young group, and on the recognition task both in the young and older groups but not in the Alzheimer group. The most important finding in the Alzheimer group is that the Self-reference led the most often to a subjective sense of remembering (especially for the positive words) with the retrieval of the correct encoding source. This Self-reference recollection effect in patients was related to independent subjective measures of a positive and definite sense of Self (measured by the Tennessee Self Concept Scale), and to memory complaints in daily life. In conclusion, these results demonstrated the power and robustness of the Self-reference effect on recollection in long-term episodic memory in Alzheimer's disease, albeit the retrieval is considerably reduced. These results should open new perspectives for the development of rehabilitation programs for memory deficits.