May 6

Hot Off the Press: Lysosomal cathepsin D is upregulated in Alzheimer’s disease neocortex and may be a marker for neurofibrillary degeneration

First authored by postgraduate student Yuek Ling, we report here our latest findings in dementia neurochemistry. Alzheimer’s disease (AD) is characterized by accumulation of β-amyloid plaques (AP) and neurofibrillary tangles (NFT) in the cortex, together with synaptic loss and amyloid angiopathy. Perturbations in the brain lysosomal system, including the cathepsin family of proteases, have been implicated in AD where they may be involved in proteolytic clearance of misfolded and abnormally aggregated peptides. However, the status of cathepsin D (catD) is unclear in Lewy body dementia, the second most common form of neurodegenerative dementia after AD, and characterized by Lewy bodies (LB) containing aggregated α-synuclein. Furthermore, earlier reports of catD changes in AD have not been entirely consistent. We measured CatD immunoreactivities in the temporal (Brodmann area BA21) and parietal (BA40) cortices of well characterized AD brains as well as two clinical subtypes of Lewy body dementia, namely Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB), known to show varying degrees of concomitant AD pathology. Increased catD immunoreactivities in AD were found for both neocortical regions measured, where they also correlated with neuropathological NFT scores and phosphorylated pSer396 tau burden, and appeared to co-localize at least partly to NFT-containing neurons. In contrast, catD was increased only in BA40 in DLB and not at all in PDD, did not correlate with LB scores, and did not appreciably co-localize with α-synuclein inclusions. Our study suggests that catD upregulation may be an adaptive response to AD-related processes leading to neurofibrillary degeneration, but may not be directly associated with formation of α-synuclein inclusions in Lewy body dementia.


Chai YL, Chong JR, Weng J, et al. (This paper).

January 11

Hot Off the Press: Mitochondrial translocase of the outer membrane (TOM) alterations may underlie dysfunctional oxidative phosphorylation in Alzheimer’s disease

The translocase of the outer membrane (TOM) is a vital mitochondrial transport system facilitating the importation of nuclear encoded proteins into the organelle. While mitochondrial dysfunction, including perturbation of oxidative phosphorylation (OXPHOS) complex, is evident in Alzheimer’s disease (AD), it remains unclear whether the observed OXPHOS deficits may be associated with TOM alterations. In this study, the objective was to correlate TOM subunits with OXPHOS complex proteins in AD. We used postmortem neocortex (BA40) from AD and age-matched controls were processed to obtain mitochondrial enriched homogenates for the measurement of Tom20, Tom22, Tom40, Tom70 as well as components of OXPHOS complex I – V by immunoblotting. We found that Tom20 and Tom70 immunoreactivities were significantly reduced in AD, as were components of OXPHOS complex I and III. Both Tom20 and Tom70 positively correlated with complex III and V, while Tom20 also correlated with complex IV. In conclusion, reductions in certain TOM subunits and their correlations with specific OXPHOS complex proteins suggest that an impaired mitochondrial transportation system may contribute to previously observed oxidative phosphorylation deficits in AD. Follow-up studies are needed to corroborate the present correlative study.


Atamna H, Frey WH, 2nd (2007) Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease. Mitochondrion 7:297-310.

Chai YL, Xing H, Chong JR et al. (This paper).

September 18

Hot Off the Press: Increased phosphorylation of collapsin response mediator protein-2 at Thr514 correlates with β-amyloid burden and synaptic deficits in Lewy body dementias

pcrmp2Collapsin response mediator protein-2 (CRMP2) regulates axonal growth cone extension, and increased CRMP2 phosphorylation may lead to axonal degeneration. Axonal and synaptic pathology is an important feature of Lewy body dementias (LBD), but the state of CRMP2 phosphorylation (pCRMP2) as well as its correlations with markers of neurodegeneration have not been studied in these dementias. Hence, we measured CRMP2 phosphorylation at Thr509, Thr514 and Ser522, as well as markers of β-amyloid (Aβ), tau-phosphorylation, α-synuclein and synaptic function in the postmortem neocortex of a longitudinally assessed cohort of LBD patients characterized by low (Parkinson’s disease dementia, PDD) and high (dementia with Lewy bodies, DLB) burden of Alzheimer type pathology. We found specific increases of pCRMP2 at Thr514 in DLB, but not PDD. The increased CRMP2 phosphorylation correlated with fibrillogenic Aβ as well as with losses of markers for axon regeneration (β-III-tubulin) and synaptic integrity (synaptophysin) in LBD. In contrast, pCRMP2 alterations did not correlate with tau-phosphorylation or α-synuclein, and also appear unrelated to immunoreactivities of putative upstream kinases glycogen synthase kinase 3β and cyclin-dependent kinase 5, as well as to protein phosphatase 2A. In conclusion, increased pCRMP2 may underlie the axonal pathology of DLB, and may be a novel therapeutic target. However, antecedent signaling events as well as the nature of pCRMP2 association with Aβ and other neuropathologic markers require further study.


Xing H, Lim YA, Chong JR, Lee JH, Aarsland D, Ballard CG, Francis PT, Chen CP, Lai MK (This paper).

February 26

Hot Off the Press: An isoform-specific role of FynT tyrosine kinase in Alzheimer’s disease

Fyn isoform AD

Recent studies suggest that Fyn tyrosine kinase forms part of a toxic triad with β-amyloid and tau in the disease process. However, it is not known whether Fyn is associated with the pathological features of AD in an isoform-specific manner. In this study, we identified selective up-regulation of the alternative-spliced FynT isoform with no change in FynB in the AD neocortex. Furthermore, gene ontology term enrichment analyses and cell type-specific localization of FynT immunoreactivity suggest that FynT up-regulation was associated with neurofibrillary degeneration and reactive astrogliosis. Interestingly, significantly increased FynT in NFT-bearing neurons was concomitant to decreased FynB immunoreactivity, suggesting an involvement of alternative splicing in NFT formation. Furthermore, cultured cells of astrocytic origin have higher FynT to FynB ratio compared to those of neuronal origin. Lastly, primary rat mixed neuron-astrocyte cultures treated with Aβ25-35 showed selective up-regulation of FynT expression in activated astrocytes. Our findings point to an isoform-specific role of FynT in modulating neurofibrillary degeneration and reactive astrogliosis in AD. Fyn kinase is known to interact with β-amyloid and tau, and contributes to Alzheimer’s disease pathogenesis. In this study, it is shown that the alternatively spliced FynT isoform is specifically up-regulated in the AD neocortex, with no change in FynB isoform. The increased FynT correlated with markers of neurofibrillary degeneration and reactive astrogliosis. In primary mixed cultures, treatment with amyloid peptides specifically up-regulated FynT in activated astrocytes. This study points to altered alternative splicing as a potential pathogenic mechanism in AD.

Fyn pTau


Lee C, Low CY, Francis PT, Attems J, Wong PT, Lai MK, Tan MG (This paper).

February 25

Hot Off the Press: Altered relaxin family receptors RXFP1 and RXFP3 in the neocortex of depressed Alzheimer’s disease patients


The G-protein-coupled relaxin family receptors RXFP1 and RXFP3 are widely expressed in the cortex and are involved in stress responses and memory and emotional processing. However, the identification of these receptors in human cortex and their status in Alzheimer’s disease (AD), which is characterized by both cognitive impairments and neuropsychiatric behaviours, have not been reported. In this study, we characterized RXFP receptors for immunoblotting and measured RXFP1 and RXFP3 immunoreactivities in the postmortem neocortex of AD patients longitudinally assessed for depressive symptoms. RXFP1 and RXFP3 antibodies were characterized by immunoblotting with lysates from transfected HEK cells and preadsorption with RXFP3 peptides. Also, postmortem neocortical tissues from behaviourally assessed AD and age-matched controls were processed for immunoblotting with RXFP1 and RXFP3 antibodies. Compared to controls, putative RXFP1 immunoreactivity was reduced in parietal cortex of non-depressed AD patients but unchanged in depressed patients. Furthermore, RXFP3 immunoreactivity was increased only in depressed AD patients. RXFP1 levels in the parietal cortex also correlated with severity of depression symptoms. In contrast, RXFP1 and RXFP3 levels did not correlate with dementia severity or β-amyloid burden. Our study suggests that alterations of RXFP1 and RXFP3 may be neurochemical markers of depression in AD, and relaxin family receptors warrant further preclinical investigations as possible therapeutic targets for neuropsychiatric symptoms in dementia.


Lee JH, Koh SQ, Guadagna S, Francis PT, Esiri MM, Chen CP, Wong PT, Dawe GS, Lai MK (This paper).

September 29

Hot Off the Press: Differential Alterations of Neocortical GluN Receptor Subunits in Patients with Mixed Subcortical Ischemic Vascular Dementia and Alzheimer’s Disease

Ezan GluN VaD MixD Fig1Glutamatergic deficits are well-established neurochemical findings in Alzheimer’s disease (AD) and are thought to underlie both cognitive and behavioral symptoms of the disease. However, it is unclear whether subcortical ischemic vascular dementia (SIVD) and mixed SIVD/AD (MixD) manifest similar changes in the glutamatergic system. In this study, we measured the immunoreactivities of NMDA receptor GluN1, GluN2A, and GluN2B subunits in SIVD and MixD in postmortem neocortical tissues from a cohort of well-characterized, longitudinally followed-up patients with SIVD and MixD, together with age-matched controls. We found a significant reduction of GluN1 only in MixD, while significant increases of GluN2A and GluN2B were found only in SIVD. Furthermore, GluN1 loss and GluN2A/2B upregulation was associated respectively with higher Braak stages and lacunar infarct scores. Our data therefore suggest that the differential alterations of GluN subunits in SIVD and MixD may result from separate, interacting disease processes, and point to the potential utility of glutamatergic approaches for pharmacotherapy.


Mohamed NE, Lee JH, Francis PT, Esiri MM, Chen CP, Lai MK (This paper).

November 14

Hot Off the Press: Decreased rabphilin 3A immunoreactivity in Alzheimer’s Disease is associated with Aβ burden

Synaptic dysfunction, together with neuritic plaques, neurofibrillary tangles and cholinergic neuron loss is an established finding in the Alzheimer’s disease (AD) neocortex. The synaptopathology of AD is known to involve both pre- and postsynaptic components. However, the status of rabphilin 3A (RPH3A), which interacts with the SNARE complex and regulates synaptic vesicle exocytosis and Ca2+-triggered neurotransmitter release, is at present unclear. In this study, we measured RPH3A and its ligand rab3A as well as several SNARE proteins in postmortem neocortex of patients with AD, and found specific reductions of RPH3A immunoreactivity compared with aged controls. RPH3A loss correlated with dementia severity, cholinergic deafferentation, and increased β-amyloid (Aβ) concentrations. Furthermore, RPH3A expression is selectively downregulated in cultured neurons treated with Aβ peptides. Our data suggest that presynaptic SNARE dysfunction forms part of the synaptopathology of AD.


Tan MG, Lee C, Lee JH, Francis PT, Williams RJ, Ramírez MJ, Chen CP, Wong PT, Lai MK (This paper).


July 29

Hot Off the Press: Decreased immunoreactivities of neocortical AMPA receptor subunits correlate with motor disability in Lewy body dementias

Dementia with Lewy bodies and Parkinson’s disease dementia are different clinical phenotypes of Lewy body dementias (LBD) differentiated by the temporal relationship between parkinsonism and dementia onset. At present, it is unclear whether the glutamatergic system is affected in these disorders. In this study, we measured α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA subunits in the postmortem neocortex of a cohort of prospectively studied Lewy body dementia cases, as well as age-matched controls by immunoblotting. We found moderate losses of GluA2/3/4 immunoreactivities in LBD which correlated with higher predeath Hoehn & Yahr scores, a measure of motor disabilities; but not with dementia severity, cortical Lewy body burden, or amyloid plaque and neurofibrillary tangle burden. Our study suggests that GluA2/3/4 losses may be a neurochemical marker of motor disability in Lewy body dementias. Given recent proposals to use AMPA receptor antagonists in Parkinson’s disease, especially for levodopa-induced dyskinesia (Johnson et al. 2009), our data suggest both potential and caution in extending such therapeutic rationales to LBD in view of altered levels of receptor drug targets.


Mohamed NE, Howlett DR, Ma L, Francis PT, Aarsland D, Ballard CG, McKeith IG, Chen CP, Lai MK (This paper).

Johnson KA, Conn PJ, Niswender CM (2009) Glutamate receptors as therapeutic targets for Parkinson’s disease. CNS Neurol Disord Drug Targets 8:475-491.