Alzheimer's disease

Research with neuropathologic or biomarker evidence of Alzheimer's disease (AD) casts doubt on traumatic brain injury (TBI) as a risk factor for AD. We leveraged the National Alzheimer's Coordinating Center to examine the association between self-reported TBI with loss of consciousness and AD neuropathologic changes, and with baseline and longitudinal clinical status.

The sample included 4761 autopsy participants (453 with remote TBI with loss of consciousness; 2822 with AD neuropathologic changes) from National Alzheimer's Coordinating Center.

Self-reported TBI did not predict AD neuropathologic changes (P > .10). Reported TBI was not associated with baseline or change in dementia severity or cognitive function in participants with or without autopsy-confirmed AD.

Self-reported TBI with loss of consciousness may not be an independent risk factor for clinical or pathological AD. Research that evaluates number and severity of TBIs is needed to clarify the neuropathological links between TBI and dementia documented in other large clinical databases 1).

Several pathway analyses of genome-wide association studies reported the involvement of metabolic and immune pathways in Alzheimer's disease (AD). Until now, the exact mechanisms of these pathways in AD are still unclear.

Chen et al., conducted a pathway analysis of a whole genome AD case-control expression dataset (n=41, 25 AD cases and 16 controls) from the human temporal cortex tissue. Using the differently expressed AD genes, they identified significant KEGG pathways related to metabolism and immune processes. Using the up- and down- regulated AD gene list, they further found up-regulated AD gene were significantly enriched in immune and metabolic pathways. They further compare the immune and metabolic KEGG pathways from the expression dataset with those from previous GWAS datasets, and found that most of these pathways are shared in both GWAS and expression datasets 2).

Dysregulation of the PI3K/Akt/mTOR signaling cascade has been associated with the pathology of neurodegeneration, specifically Alzheimer's disease (AD). Both in vivo models and post-mortem brain samples of individuals with AD have commonly shown hyperactivation of the pathway.

In the study of Hodges et al., examined how neuron subset-specific deletion of Pten (NS-Pten) in mice, which presents with hyperactive mammalian target of rapamycin (mTOR) activity, affects the hippocampal protein levels of key neuropathological hallmarks of AD. They found NS-Pten knockout (KO) mice to have elevated levels of amyloid-β, α-synuclein, neurofilament-L, and pGSK3α in the hippocampal synaptosome compared with NS-Pten wild type mice. In contrast, there was a decreased expression of amyloid precursor protein, tau, GSK3α, and GSK3β in NS-Pten KO hippocampi. Overall, there were significant alterations in levels of proteins associated with AD pathology in NS-Pten KO mice. This study provides novel insight into how altered mTOR signaling is linked to AD pathology, without the use of an in-vivo AD model that already displays neuropathological hallmarks of the disease 3).

Pathologies and dementias of the nervous system such as Alzheimer disease can result when tau proteins become defective and no longer stabilize microtubules properly.

Microtubule-associated protein tau is the major component of paired helical filaments (PHFs) associated with the neuropathology of Alzheimer's disease (AD). Tau in the normal brain binds and stabilizes microtubules. Tau isolated from PHFs is hyperphosphorylated, which prevents it from binding to microtubules. Tau phosphorylation has been suggested to be involved in the development of NFT pathology in the AD brain. Recently, we showed that 14-3-3ζ is bound to tau in the PHFs and when incubated in vitro with 14-3-3ζ, tau formed amorphous aggregates, single-stranded straight filaments, double stranded ribbon-like filaments and PHF-like filaments that displayed close resemblance with corresponding ultrastructures of AD brain. Surprisingly however, phosphorylated and non-phosphorylated tau aggregated in a similar manner, indicating that tau phosphorylation does not affect in vitro tau aggregation (Qureshi et al (2013) Biochemistry 52, 6445-6455). In this study, we have examined the role of tau phosphorylation in tau aggregation in cellular level. We have found that in human M17 neuroblastoma cells, tau phosphorylation by GSK3β or PKA does not cause tau aggregation, but promotes 14-3-3ζ-induced tau aggregation by destabilizing microtubules. Microtubule disrupting drugs also promoted 14-3-3ζ-induced tau aggregation without changing tau phosphorylation in M17 cell. In vitro, when incubated with 14-3-3ζ and microtubules, nonphosphorylated tau bound to microtubules and did not aggregate. Phosphorylated tau on the other hand did not bind to microtubules and aggregated. Our data indicate that microtubule-bound tau is resistant to 14-3-3ζ-induced tau aggregation and suggest that tau phosphorylation promotes tau aggregation in the brain by detaching tau from microtubules and thus making it accessible to 14-3-3ζ 4).

It has been suggested by multiple previous studies that a bunch of AD key influencing factors might be attributed to genes encoding human leukocyte antigen (HLA), whose variety is an essential part of human adaptive immunity. A wide range of activities involved in immune responses may be determined by HLA genes, including inflammation mediated by the immune response, T-cell transendothelial migration, infection, brain development and plasticity in AD pathogenesis, and so on. The goal of a article of Wang et al. was to review the recent epidemiological findings of HLA (mainly HLA class I and II) associated with AD and investigate to what extent the genetic variations of HLA were clinically significant as pathogenic factors for AD. Depending on the degree of contribution of HLA in AD pathogenesis, targeted research towards HLA may propel AD therapeutic strategies into a new era of development 5).

Mutations in the Presenilin 1 (PSEN1) gene are the most common cause of autosomal dominant familial Alzheimer's disease 6).

Alzheimer's disease clinical features.

Alzheimer's disease biomarkers.

Alzheimer's disease treatment.

Alzheimer disease (AD)-related pathology was assessed in cortical biopsy samples of 111 patients with idiopathic normal pressure hydrocephalus. Alzheimer disease hallmark lesions-amyloid beta (Aβ) and hyperphosphorylated tau (HPtau)-were observed in 47% of subjects, a percentage consistent with that for whole-brain assessment reported postmortem in unselected cohorts. Higher-immunostained area fraction of AD pathology corresponded with lower preoperative mini-mental state examination scores. Concomitant Aβ and HPtau pathology, reminiscent of that observed in patients with AD, was observed in 22% of study subjects. There was a significant correlation between Aβ-immunostained area fraction in tissue and Aβ42 (42-amino-acid form of Aβ) in cerebrospinal fluid (CSF). Levels of Aβ42 were significantly lower in CSF in subjects with concomitant Aβ and HPtau pathology compared with subjects lacking pathology. Moreover, a significant correlation between HPtau-immunostained area fraction and HPtau in CSF was noted. Both HPtau and total tau were significantly higher in CSF in subjects with concomitant Aβ and HPtau pathology compared with subjects lacking pathology. The 42-amino-acid form of Aβ (Aβ42) and HPtau in CSF were the most significant predictors of the presence of AD pathology in cortical biopsies. Long-term follow-up studies are warranted to assess whether all patients with idiopathic normal-pressure hydrocephalus with AD pathology progress to AD and to determine the pathologic substrate of idiopathic normal-pressure hydrocephalus 7).

Sugarman MA, McKee AC, Stein TD, Tripodis Y, Besser LM, Martin B, Palmisano JN, Steinberg EG, O'Connor MK, Au R, McClean M, Killiany R, Mez J, Weiner MW, Kowall NW, Stern RA, Alosco ML. Failure to detect an association between self-reported traumatic brain injury and Alzheimer's disease neuropathology and dementia. Alzheimers Dement. 2019 Mar 6. pii: S1552-5260(19)30009-3. doi: 10.1016/j.jalz.2018.12.015. [Epub ahead of print] PubMed PMID: 30852157.
Chen J, Xie C, Zhao Y, Li Z, Xu P, Yao L. Gene expression analysis reveals the dysregulation of immune and metabolic pathways in Alzheimer's disease. Oncotarget. 2016 Oct 6. doi: 10.18632/oncotarget.12505. PubMed PMID: 27732949.
Hodges SL, Reynolds CD, Smith GD, Jefferson TS, Nolan SO, Lugo JN. Molecular interplay between hyperactive mammalian target of rapamycin signaling and Alzheimer's disease neuropathology in the NS-Pten knockout mouse model. Neuroreport. 2018 Jun 29. doi: 10.1097/WNR.0000000000001081. [Epub ahead of print] PubMed PMID: 29965873.
Li T, Paudel HK. 14-3-3ζ Mediates Tau Aggregation in Human Neuroblastoma M17 Cells. PLoS One. 2016 Aug 22;11(8):e0160635. doi: 10.1371/journal.pone.0160635. eCollection 2016. PubMed PMID: 27548710.
Wang ZX, Wan Q, Xing A. HLA in Alzheimer's Disease: Genetic Association and Possible Pathogenic Roles [published online ahead of print, 2020 Sep 7]. Neuromolecular Med. 2020;10.1007/s12017-020-08612-4. doi:10.1007/s12017-020-08612-4
O'Connor A, Abel E, Fraser MR, Ryan NS, Jiménez DA, Koriath C, Chávez-Gutiérrez L, Ansorge O, Mummery CJ, Lashley T, Rossor MN, Polke JM, Mead S, Fox NC. A novel presenilin 1 duplication mutation (Ile168dup) causing Alzheimer's disease associated with myoclonus, seizures and pyramidal features. Neurobiol Aging. 2021 Feb 5:S0197-4580(21)00046-4. doi: 10.1016/j.neurobiolaging.2021.01.032. Epub ahead of print. PMID: 33648786.
Elobeid A, Laurell K, Cesarini KG, Alafuzoff I. Correlations Between Mini-Mental State Examination Score, Cerebrospinal Fluid Biomarkers, and Pathology Observed in Brain Biopsies of Patients With Normal-Pressure Hydrocephalus. J Neuropathol Exp Neurol. 2015 May;74(5):470-479. PubMed PMID: 25868149.
  • alzheimer_s_disease.txt
  • Last modified: 2021/04/26 09:37
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