Alzheimer’s Disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia that generally initiates with subtle failure of memory, progressing over years to an incapacitating level. Approximately 25 % of all AD is familial of which approximately 95 % is late-onset (age >60-65 years) and 5 % is early-onset (age <60 years).

Learn more about 3 key protein in Alzheimer?s Disease: Amyloid-? (A?) Precursor Protein (APP), Microtubule-associated protein tau (MAPT-Tau), Macrophage scavenger receptor 1 (MSR1).

Key genes associated with Alzheimer?s Disease

APP BACE1 BACE2 PSEN1 PSEN2 UBQLN1 APPBP1 APPBP2 ApoE ApoER2 CLU ACT BDNF CDK5R1 KCNIP1 KCNIP3 MAPT NEFM Bax IL1A IL1B KLK6 MSR1 MEOX2 NQO1

Amyloid-? (A?) Peptide

Amyloid-? (A?) Peptide image
Immunofluorescent staining of HeLa cells using anti-APP mouse monoclonal antibody Cat # TA500973.

Amyloid-? (A?) Peptide image2
Immunofluorescent analysis of Hela cells, using Ubiquilin1 Antibody Cat # TA302119 (green). Cytoplasmic actin was counterstained in red.

Apolipoprotein E receptor 1 (ApoER2)

Amyloid-? (A?) Peptide image
Immunohistochemical staining of paraffin-embedded Human lymph node tissue within the normal limits using anti-CLU mouse monoclonal antibody Cat # TA808665.

The generation of the Amyloid-? (A?) peptide through the proteolytic processing of the Amyloid precursor protein (APP) is a central event in the pathogenesis of AD. Extracellular accumulation of A? leads to formation of aggregates, fibrils and eventually amyloid deposits called neuritic plaques, a hallmark of AD. The A? peptide has neurotoxic effects and AD research has been focused on determining the underlying mechanisms of A? protein toxicity.

Established candidates for the cleavage of APP to A? are the ?-secretases BACE1 and BACE2 and Presenilin 1 and 2, which resemble the catalytic subunit of the ?-secretase complex. PEN2 (presenilin enhancer 2) is the regulatory component of the ?-secretase complex.

APP ApoE ApoER2 APPBP1 APPBP2 BACE1 BACE2 CLU PSEN1 PSEN2 UBQLN1

Ubiquilin 1 (UBQLN1) is a ubiquitin-like protein, which has been shown to play a central role in regulating the proteasomal degradation of various proteins, including the presenilins. A role for UBQLN1 steady-state levels in affecting APP trafficking and processing has been proposed, thereby influencing the generation of A?.

Amyloid protein-binding protein 1 (APPBP1) and Amyloid protein-binding protein 2 (APPBP2) interact with APP and are functionally associated with APP transport and/or processing.

Three alleles for Apolipoprotein E (ApoE) are known and there is a strong association of one or two copies of the ApoE allele e4 with late-onset AD, although the mechanism by which this allele impacts AD remains unproven.

(ApoER2) is a member of the LDL receptor family that is highly expressed in the brain. It has been shown that ApoER2 expression stimulates A? production by enhanced ?- and ?-secretase mediated amyloidogenic processing.

Clusterin/Apolipoprotein J (Apo J) has also been identified as a potential risk gene in AD. Elevated protein levels are found in the CNS under some neuropathological conditions, such as AD, where Apo J is associated with A? plaques.

Microtubule-associated protein tau (MAPT-Tau)

Microtubule-associated protein tau (MAPT-Tau) image
Immunohistochemical staining of paraffin-embedded Human breast tissue using anti-MAPT mouse monoclonal antibody Cat # UM800131.

Microtubule-associated protein tau (MAPT-Tau) image2
Staining of KCNIP1 in adult rat hippocampus with Cat # 73-003.
Microtubule-associated protein tau (MAPT-Tau) image3
Immunohistochemical staining of mouse cerebellum with Anti-BDNF rabbit polyclonal antibody Cat # TA328615. A. BDNF (red) appears in Purkinje cells (upward pointing arrows) and is distributed diffusely in the molecular layer (Mol) including in astrocytic fibers (downward pointing arrows in C). B. staining of astrocytic fibers with glial fibrillary acidic protein (green) in the same section demonstrates the distribution of BDNF to neuronal as well as to astrocytic cellular components. C. Confocal merge of BDNF and GFAP.

MAPT/Tau is a neuronal microtubule associated protein and it promotes tubulin polymerization and stabilizes microtubules. In its hyperphosphorylated form, tau is the major component of paired helical filaments and neurofibrillary lesions in AD brain. Hyperphosphorylation impairs the microtubule binding function of tau, resulting in the destabilization of microtubules in AD brains, ultimately leading to the degeneration of the affected neurons.

Key genes associated with MAPT/Tau

ACT BDNF CDK5R1 KCNIP1 KCNIP3 MAPT NEFM

Cyclin-dependent kinase 5 activator 1 (CDK5R1) activates CDK5, which is required for proper development of the central nervous system. CDK5R1 is cleaved from a p35 into a p25 form and has been shown to accumulate in neurons of patients with AD. This accumulation correlates with an increase in CDK5 activity and may lead to aberrantly phosphorylated forms of MAPT/TAU, which contributes to AD.

Alpha 1-antichymotrypsin (ACT) has been shown to promote A? polymerization and levels of ACT protein in plasma and cerebrospinal fluid from Alzheimer?s patients have been found to correlate with progression of dementia. ACT may lead to hyperphosphorylation of tau thereby enhancing degeneration of neurons.

Calsenilin/KCNIP3 and KCNIP1/VABP are members of the family of voltage-gated potassium channel-interacting proteins. They interact with presenilin 1 and 2 and are implicated in the mediation of A? formation.

Brain-derived neurotrophic factor (BDNF) belongs to so-called neurotrophins and supports the survival of existing neurons and encourages the growth and differentiation of new neurons. Neurotrophins are thought to have a protective role against A? toxicity.

Detection of Neurofilament M can be used in studies to visualize neurofilament accumulation as it can be seen in AD.

Macrophage scavenger receptor 1 (MSR1/CD204)

image
Immunohistochemical staining of paraffin-embedded Adenocarcinoma of Human endometrium tissue using anti-IL1B mouse monoclonal antibody Cat # TA506443.

image2
Immunofluorescence staining of U2OS cells with anti-NQO1 mouse monoclonal antibody Cat # TA301418 in green. Nuclei are shown in blue and beta-tubulin in red.

In Alzheimer?s disease, MSR1/CD204 is is increased. Findings of CD204 mediated adhesion and endocytosis of fibrillar A? by microglia and astrocytes suggest a role for this receptor in neuronal homeostasis and neuropathology.

Key genes associated with MSR1/CD204

Bax IL1A IL1B KLK6 MSR1 MEOX2 NQO1

Interleukin 1 is a cytokine which is overexpressed in the AD brain. This correlates to plaque formation and progression by leading to excessive expression of neuronal APP and other plaque-associated proteins and to nonsensical growth of dystrophic neuritis. Polymorphism in the IL-1A and IL-1B genes are discussed for early age onset AD.

Kallikrein-6 is a serin protease and abnormal levels have been found in patients with AD. The potential role of Kallikrein-6 as a biomarker for AD is under investigation and it has been reported that this protein might play a role in the degradation of A? or turnover of APP.

Homeobox protein MOX-2 (MEOX2) is a regulator of vascular differentiation and its expression is low in AD. It has been shown that restoring expression of the protein stimulates angiogenesis, suppresses apoptosis and increases the levels of a major A? clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP), at the blood-brain barrier.

Bax, a pro-apoptotic protein belonging to the Bcl-2 family, promotes increased apoptosis leading to enhanced neuronal degeneration in progression of AD. Bax may play a similar role in Huntington's disease.

NQO1 : While in AD there is abundant evidence for the involvement of oxidative stress, the cause or the consequences are largely unresolved.

NAD(P)H dehydrogenase (quinone 1) (NQO1), a redox-regulated flavoenzyme, plays a central role in monitoring cellular redox state and has been shown to be increased in AD.

References